Macromolecular Drugs (including monoclonal antibodies, recombinant proteins, and nucleic acid therapies) have become a cornerstone strategy for intervening in complex pathological mechanisms such as cancer, autoimmune diseases, and genetic disorders due to their high specificity for disease targets and low off-target toxicity. However, compared to traditional small-molecule drugs, the high molecular weight (>10 kDa) and structural complexity of macromolecular drugs result in extremely low transmembrane permeability. This is particularly challenging in the treatment of central nervous system (CNS) diseases, where the blood-brain barrier (BBB) imposes stringent selectivity, further limiting drug delivery efficiency. This review focuses on the breakthrough strategy of nose-to-brain (NtB) drug delivery. On one hand, the NtB pathway bypasses the BBB, enabling direct CNS drug delivery. On the other hand, nanocarrier technology can synergistically achieve systemic delivery and brain-targeted transport. Based on the latest research advances, this article systematically examines the feasibility of delivering macromolecular drugs via NtB administration. We comprehensively summarize relevant delivery carriers and discuss the potential advantages of intranasal-brain delivery for CNS disease treatment. Notably, while significant progress has been made in this field, further exploration is still needed regarding the mechanisms of NtB delivery and challenges in clinical translation.

Real-life data regarding inflammatory bowel disease (IBD) evolution after switch from intravenous infliximab (IV-IFX) to subcutaneous infliximab (SC-IFX) is necessary. The aim of this prospective multicenter cohort study was to describe the persistence, effectiveness and tolerance of SC-IFX after switch from IV-IFX.

IBD patients in steroid-free clinical remission for at least 6 months on IV-IFX were enrolled in a prospective national French cohort when they switched to SC-IFX. Patients were assessed at inclusion and at weeks 12, 24, and 48. The primary endpoint was the persistence of SC-IFX at week 48. Secondary endpoints comprised steroid-free clinical remission at week 48, IV-IFX switch-back rate, and evolution of infliximab levels during the study period.

Among the 426 patients included (72.4% with Crohn's disease , 27.5% with ulcerative colitis; 45.1% female; median age 37 [interquartile range, 29-50] years; median disease duration of 12 years in Crohn's disease, 13 years in ulcerative colitis), 56% were on IV-IFX standard dosing (5 mg/kg 8-weekly) and 16% received combination therapy with an immunomodulator drug at baseline. At week 48, SC-IFX persistence was 95.4% (95% confidence interval, 93.3%-97.5%) and 86.9% of patients were on steroid-free clinical remission. Mean infliximab levels were 8.0 μg/mL at inclusion and 18.0 μg/mL at week 48 (P < .0001). Among the 19 (4.5%) patients who stopped SC-IFX, 6 (1.4%) switched back to IV-IFX. There were 222 adverse events reported in 42.4% of patients, and 12 led to treatment discontinuation, including 6 (1.4%) severe adverse events.

In this large multicenter prospective cohort, persistence at 1 year of SC-IFX was more than 95% of IBD patients switched in remission from IV-IFX, confirming excellent effectiveness and tolerance of SC-IFX.

Infliximab treatment failure in patients with inflammatory bowel disease may result from sub-optimal infliximab trough level. An understanding of pharmacokinetics (PKs) is important to maintain an optimal trough level. PK studies of the switch to subcutaneous (SC) infliximab from intravenous (IV) infliximab using real-world data are lacking. We aimed to develop a population PK model of IV and SC infliximab to predict individual infliximab exposure during maintenance therapy.

We used data from prospectively collected data on IV and SC infliximab concentrations in patients with inflammatory bowel disease receiving maintenance treatment from February 2020 to December 2022 at Samsung Medical Center. Population PK analysis was conducted by using a two-compartment model with first-order absorption and first-order elimination. Goodness-of-fit plots and visual predictive check were used to evaluate the PK model.

A total of 2,132 samples from 181 patients (149 Crohn's disease and 32 ulcerative colitis) were analyzed. We developed an infliximab population PK model using body mass index, albumin, C-reactive protein level, and the anti-drug antibody level and validated its predictive performance.

It may be possible to predict the infliximab trough level of both IV and SC infliximab in patients with inflammatory bowel disease during maintenance treatment by using our model in real-world practice.

Intravenous (IV) infliximab (IFX) combined with an immunomodulator (combination therapy) outperforms IV IFX monotherapy in terms of clinical, endoscopic, and immunogenicity outcomes in patients with inflammatory bowel disease (IBD). With the advent of subcutaneous (SC) IFX, which is associated with higher serum drug concentrations, it is essential to assess whether SC IFX monotherapy provides similar pharmacokinetic and clinical benefits as combination therapy.

We conducted a systematic review and meta-analysis (until August 2024), of studies on patients with IBD treated with SC IFX. The primary outcome was anti-drug antibodies (ADAs) formation within 12 months (M) after starting SC IFX or after switching from IV to SC IFX. Secondary outcomes included treatment persistence, clinical efficacy, and biochemical parameters.

Twenty-four studies (n = 3172) were included. Among patients transitioning from IV IFX induction to SC IFX, immunogenicity was more prevalent with monotherapy than combination treatment (median, 68% vs 48%; odds ratio [OR], 3.29; 95% confidence interval [CI], 1.71-6.31; P < .001). Clinical response rates at 12M were comparable, with a trend favoring combination therapy (OR, 0.73; 95% CI, 0.50-1.06; P = .10). In patients switching from IV maintenance to SC IFX, relapse rates were low (median, 12% at 6M, 11% at week 50), with stable biochemical markers. Treatment persistence was high (93% at 6M, 92% at 12M). Among patients with quiescent disease at the time of switching, 1-year relapse rates were 9% to 11%, with baseline immunogenicity predicting treatment failure.

SC IFX monotherapy is associated with higher immunogenicity rates compared with combination therapy, particularly in new IFX starters. Although clinical response was comparable, a trend favoring combination therapy warrants further investigation.

The estimand framework, introduced in the ICH E9 (R1) Addendum, provides a structured approach for defining precise research questions in randomised clinical trials. It suggests five strategies for addressing intercurrent events (ICE). This case study examines the principal stratum strategy, highlighting its potential for estimating causal treatment effects in specific subpopulations and the challenges involved. The occurrence of anti-drug antibodies (ADAs) and their potential clinical impact are important factors in evaluating biosimilars. Typically, analyses focus on subgroups of patients who develop ADAs during the study. However, conducting subgroup analyses based on post-randomisation variables, such as immunogenicity, can introduce substantial bias into treatment effect estimates and is therefore methodologically not optimal. The principal stratum strategy provides a statistical pathway for estimating treatment effects in subpopulations that cannot be anticipated at baseline. By leveraging counterfactuals to assess treatment outcomes, with and without the incidence of intercurrent events (ICEs), this approach can be implemented through a missing data perspective. We demonstrate the implementation of the principal stratum strategy in a phase 3 equivalence trial of a biosimilar for the treatment of rheumatoid arthritis. Using a multiple imputation approach, we leverage longitudinal measurements to create analysis datasets for subpopulations who develop ADAs as ICE. Our results highlight the principal stratum strategy's potential and challenges, emphasising its reliance on unobserved ICE states and the need for complex and rigorous modelling. This study contributes to a nuanced understanding and practical implementation of the principal stratum strategy within the ICH E9 (R1) framework.

Superior efficacy of subcutaneous infliximab (CT-P13 SC) over placebo for maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC) was demonstrated in the randomized LIBERTY-CD and LIBERTY-UC studies. The current post hoc analysis compared outcomes with CT-P13 SC by baseline immunosuppressant use.

Patients with moderately to severely active CD or UC randomized to the CT-P13 SC maintenance arm of the 54-week LIBERTY trials at week 10 and who were treated in the open-label extension (weeks 56-102) were included. Pharmacokinetic, efficacy, biomarker, safety, and immunogenicity endpoints were evaluated by baseline immunosuppressant use (monotherapy vs combination therapy).

A total of 192 patients with CD (monotherapy, n = 126; combination therapy, n = 66) and 237 patients with UC (monotherapy, n = 180; combination therapy, n = 57) were included. In both studies, efficacy outcomes were generally comparable between monotherapy and combination therapy at week 54 or week 102. Serum concentrations were generally higher, and antidrug antibody-positive conversion rates were lower, with combination therapy relative to monotherapy. In combined analyses of CD and UC, comparable safety profiles were observed between monotherapy and combination therapy.

Despite some differences in pharmacokinetics and immunogenicity between CT-P13 SC received alone or in combination with immunosuppressants in patients with CD or UC, efficacy outcomes at week 54 or week 102 were generally comparable. The overall safety profile and incidence of systemic injection reactions were also comparable between monotherapy and combination therapy.

Elective switching from intravenous (IV) to subcutaneous (SC) infliximab (IFX) has shown efficacy in patients with inflammatory bowel disease (IBD). However, long-term outcomes for patients not in remission remain unclear.

We evaluated the effectiveness of SC IFX switching in both remission and non-remission patients.

This study was a retrospective multicentre study conducted across five tertiary hospitals in Korea.

Patients with IBD who switched to SC IFX between January 2021 and January 2023 were included. Clinical remission was defined as a Crohn's Disease Activity Index of <150 or a partial Mayo score of <2. Biochemical remission was defined as faecal calprotectin of <250 µg/g and C-reactive protein of <0.5 mg/dL. We investigated the treatment persistence rate of SC IFX and trends in pharmacokinetics, clinical indices and biomarkers over 1 year of follow-up, analysing the data based on the baseline remission state.

Among 127 patients included, 90 (70.9%) were in clinical remission, and 37 (29.1%) were not at the time of switching. The one-year treatment persistence rate was 92.1%, with no significant difference between the clinical remission and non-remission groups (p = 0.139). Persistence was also unaffected by baseline biochemical remission status. IFX pharmacokinetics and biomarkers improved significantly in both clinical groups over 12 months (p < 0.005). Disease activity indices remained stable in the remission group and decreased in the non-remission group after switching. Previous biologics exposure was the only significant predictor of treatment persistence (hazard ratio, 5.634; 95% confidence interval, 1.357-23.384; p = 0.017). Adverse events related to SC IFX occurred in 15.7% of patients. The optimal SC IFX cutoff levels associated with clinical and biochemical remission were 11 and 17 μg/mL, respectively.

Switching from IV to SC IFX during maintenance therapy demonstrated high treatment persistence and safety, irrespective of clinical and biochemical remission status.

A subcutaneous formulation of infliximab was recently approved for maintenance therapy of inflammatory bowel disease (IBD). However, limited clinical experience, particularly with patients on escalated intravenous infliximab regimens, poses challenges for the transition to subcutaneous therapy. We investigated the pharmacokinetics and pharmacodynamics of subcutaneous infliximab to identify early predictors of relapse on switching.

We repurposed data from a prospective, multicenter trial involving patients with IBD switching from intravenous to subcutaneous infliximab. We estimated each patient's infliximab clearance using Bayesian forecasting from a preswitch sample and a population pharmacokinetics model. We performed pharmacodynamics modeling to evaluate preswitch predictors of postswitch relapse. Relapse was defined as clinical recurrence (partial Mayo score >2 or Harvey-Bradshaw Index >4 leading to therapeutic escalation) or an increase in fecal calprotectin ≥150 μg/g on switching.

Using data from 98 patients with IBD, we identified infliximab clearance and fecal calprotectin as independent predictors of relapse. A 2-item risk score stratified patients into the low-risk (<19% probability of relapse; 75/98; 77%) and high-risk (≥19% probability of relapse; 23/98; 23%) groups (sensitivity 0.75 [95% CI 0.48-0.93], specificity 0.87 [95% CI 0.77-0.93] positive predictive value 52% [95% CI 31-73%], negative predictive value 95% [95% CI 87-99%]). Our pharmacokinetics-pharmacodynamics model classified patients with and without relapse ( P < 0.0001) with an area under the receiver operating characteristic curve of 0.83 (95% CI 0.71-0.93).

Preswitch infliximab clearance and fecal calprotectin are accurate predictors of relapse after switching to subcutaneous infliximab. An interactive risk stratification tool facilitates confirmation of a stratified medicine approach to improve infliximab therapy in IBD.

Inflammatory bowel disease (IBD) is a multifactorial illness with a climbing prevalence worldwide. While biologics are commonly prescribed especially for severe cases, they may worsen patients' outcomes due to financial burden. Consequently, there has been an increased focus on biosimilars to improve overall disease outcomes by maintaining similar efficacy and safety while minimizing the cost of therapy. Infliximab-dyyb was the first biosimilar approved by US-FDA for IBD. Since that, the US-FDA approved 14 biosimilars with different mechanisms of action and different routes of administration for IBD patients (four infliximab biosimilars, nine adalimumab biosimilars, and most recently one ustekinumab biosimilar). It should be noted that more biologics are in the pipeline as golimumab and natalizumab patents are set to expire in the near future, and biosimilars are now in pre-clinical to phase 3 trials. Different studies have evaluated biologics' effectiveness and safety and concluded that the majority of available biosimilars are efficacious and have similar adverse effect profiles compared to their reference biologics. It is worth mentioningthat post-marketing surveillance reports revealed some risks associated with biosimilars which should be taken into consideration in future research and clinical trials to avoid health hazards. Most biologics and biosimilars are administered parenterally which results in several drawbacks such as raised risk of infections, hypersensitivity, autoimmunity, development of malignancies, liver toxicity as well as worsening of heart failure. Several drug delivery systems based on passive and active targeting mechanisms are under active investigation to overcome these limitations. This review sheds light on the emergence of biologics and biosimilars as alternatives in IBD management, the differences between them, challenges and risks, and future perspectives in IBD therapy and new trends in drug delivery systems.

Therapeutic drug monitoring of infliximab is commonly performed based on trough concentration. However, doses and dosing intervals may be adapted to patient outcomes, and this trough concentration target may correspond to a large range of exposures in terms of the area under the concentration-time curve (AUC). The objectives of this study were to assess the real-life exposure to intravenous infliximab in patients with Crohn disease in remission at year 1 and to assess the evolution of exposure in patients who switched to subcutaneous infliximab.

The authors conducted a retrospective observational pharmacokinetic study in patients with Crohn disease who had available infliximab concentrations during intravenous and subcutaneous infliximab maintenance therapy as per the standard of care. Infliximab exposure parameters (AUCs and trough concentrations, C 0 ) were compared for different dosing regimens of intravenous infliximab before (intravenous) and after (subcutaneous) the switch.

A total of 113 patients had 383 intravenous infliximab concentrations. Dosing intervals ranged from 4 to 12 weeks. The median/range/CV% C 0 , AUC 0-t , and AUC 0-8weeks were 5.3 mcg/mL [

CONCLUSIONS

In this study, the authors suggested that in patients treated with IV IFX, different targets of C 0 should be proposed according to treatment schemes and that AUC 0-t might be a relevant determinant of clinical remission. Moreover, exposure did not remain stable throughout the switch from IV to SC IFX in any patient. These variations may depend on the intravenous dosing interval before switching.

Collapse

Recent studies suggest that subcutaneous infliximab is effective and safe for treating patients with inflammatory bowel disease. Real-world studies with larger cohorts are needed to confirm the efficacy of subcutaneous treatment.

The aim was to assess real-world treatment persistence, clinical outcomes, infliximab concentrations, and treatment safety after switching from intravenous to subcutaneous infliximab treatment with patients with inflammatory bowel disease.

This retrospective register-based study included patients with inflammatory bowel disease who were in clinical remission and switched from intravenous infliximab maintenance therapy to subcutaneous infliximab in two tertiary centers.

A total of 274 patients (104 Crohn's disease and 170 ulcerative colitis) were included. After the switch, the treatment persistence at 12 months was 94.8% in patients with Crohn's disease and 88.8% in patients with ulcerative colitis. Only 11.3% (n = 31) of the patients discontinued the treatment during 79-week median follow-up. Compared to the baseline, no change occurred in clinical disease activity at the time points of 3, 6, and 12 months, based on the Harvey-Bradshaw Index or partial Mayo Score (p = 0.792 and p = 0.426, respectively). Infliximab median concentrations were higher (p < 0.0001) during subcutaneous treatment (16.75 µg/ml) compared to the intravenous treatment median trough levels before the switch (6.71 µg/ml). In total, 15.0% (n = 41) of the patients reported adverse events.

Switching to subcutaneous infliximab maintenance therapy was associated with high treatment persistence, a stable disease course, increased infliximab concentrations, and an acceptable safety profile.

Background/Objectives: Interleukin 12/23 inhibitors are a newer class of monoclonal antibodies used to induce and maintain remission for Crohn's disease (CD), a chronic inflammatory bowel disease, when patients do not respond to conventional immunomodulatory drugs or first-line monoclonal antibody therapies. Although biologics are best administered intravenously, subcutaneous administration has been trialed, with mixed results. This research synthesized evidence on the efficacy and safety of subcutaneous compared to intravenous administration of interleukin 12/23 inhibitors for moderate to severe CD. Methods: In this systematic review and meta-analysis, we searched Cochrane, PubMed, SCOPUS, CINHAL, and preprint archives for randomized controlled trials (RCTs) that compared the efficacy and safety of subcutaneous to intravenous interleukin 12/23 inhibitors for the remission of CD. After study quality assessment, a meta-analysis was carried out using a bias-adjusted inverse variance heterogeneity model, heterogeneity was assessed using I2, and publication bias was performed using Doi plots. Evidence certainty was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Results: Seven RCTs, with 2179 participants, all with moderate to severe CD, were included. After meta-analysis, subcutaneous compared to intravenous administration showed similar efficacy for the induction of remission (OR 0.77, 95%CI 0.53-1.12), with no-to-low heterogeneity (I2 = 0%, p = 0.97). For the maintenance of remission, only two studies had analyzable data, and they showed that subcutaneous interleukin 12/23 inhibitors were equal or better compared to intravenous administration. Further syntheses showed that subcutaneous compared to intravenous administration of interleukin 12/23 inhibitors had almost similar odds of adverse events (OR 0.91, 95%CI 0.63-1.32, I2 = 39%), serious adverse events (OR 0.97, 95%CI 0.61-1.53, I2 = 0%), and treatment discontinuation (OR 1.06, 95%CI 0.67-1.68, I2 = 0%). Conclusions: In individuals with moderate to severe CD, subcutaneous administration has similar efficacy for inducing remission with comparable safety. More RCTs are needed to confirm these findings.

The primary objectives of the management of patients with inflammatory bowel disease (IBD) are to prevent IBD flares, prevent/delay disease progression and improve patients' quality of life. To this end, one needs to identify risk factor(s) associated with flare-ups and disease progression. We posit that disruption of circadian rhythms is one of the key factors that is associated with risk of flare-up and disease progression. This hypothesis is based on published studies that show: (1) The circadian rhythm regulates many biological processes including multiple IBD-relevant biological processes that are critical in inflammatory/immune processes such as environment/microbe interaction, microbe/host interaction, intestinal barrier integrity and mucosal immunity-all central in the pathogenesis of IBD, and (2) Circadian machinery is the primary tool for the host to interact with the environment. Circadian misalignment results in a loss of preparedness of the host to respond and adjust to the environmental changes that could make the host more vulnerable to IBD flare-ups. In this review, we first provide an overview of circadian rhythms and its role in healthy and disease states. Then we present data to support our hypothesis that: (1) IBD patients have disrupted circadian rhythms ("social jet lag") and (2) circadian misalignment and associated disrupted sleep decreases the resiliency of IBD patients resulting in microbiota dysbiosis, more disrupted intestinal barrier integrity and a more aggressive disease phenotype. We also show that circadian-directed interventions have a potential to mitigate the deleterious impact of disrupted circadian and improve IBD disease course.

Immunogenicity of biologic agents for inflammatory bowel disease (IBD) is a critical issue, especially for tumor necrosis factor (TNF) inhibitors, where anti-drug antibodies (ADAs) significantly impact drug clearance, efficacy, and safety. Studies have demonstrated that non-TNF biologics tend to have lower susceptibility to immunogenicity, potentially offering advantages, especially in long-term management. Understanding these differences is important for optimizing IBD treatment outcomes.

This review examines immunogenicity associated with different classes and individual biologic agents used in IBD; including TNF inhibitors and biologics targeting integrins and interleukins. We discuss key factors influencing ADAs formation, including drug structure, route of administration, and patient-specific factors. The literature reviewed includes recent clinical studies and long-term trials focusing on strategies to reduce immunogenicity such as therapeutic drug monitoring (TDM) and advanced combination.

While newer biologics demonstrate lower immunogenicity compared to anti-TNF agents, challenges remain in management to overcome existing ADAs responses while advances in genetic profiling, point-of-care TDM, and combination therapies offer promising pathways to reduce immunogenicity and enhance treatment durability. Continued research and innovation in biologic delivery methods, such as oral and subcutaneous formulations, will be critical in the next decade to further mitigate immunogenic risks and improve patient outcomes.

This study investigates the alarming epidemiological trends of inflammatory bowel disease (IBD) among children and young adults, highlighting the associated disease burden on global health.

Utilizing data from the Global Burden of Disease (GBD) study 2021, we conducted a comprehensive analysis of age-standardized incidence rates (ASIR), age-standardized mortality rates (ASMR), disability-adjusted life years (DALYs), and estimated annual percentage changes (EAPC). Future trends were forecasted using the Bayesian age-period-cohort model.

From 1990 to 2021, IBD incidence and DALY rates remained persistently high, with a concerning upward trend noted among children and young adults. While men experienced a decline in DALY rates, women faced increasing burdens. In 2021, high-income regions, particularly North America, reported the highest incidence and DALY rates, contrasting sharply with Central Latin America, which exhibited the lowest ASIR. Southeast Asia presented the most favorable DALY rates. A notable negative correlation was identified between DALY rates and socio-demographic index (SDI) at the national level, with high and high-middle SDI countries continuing to bear a substantial burden, while low and middle SDI nations faced rising challenges.

The persistent high burden of IBD in children and young adults signifies a critical public health concern. The marked geographical and gender disparities underscore the urgent need for tailored regional and population-based strategies aimed at primary prevention and effective management. This study illuminates the pressing necessity for policy interventions to address the growing epidemic of IBD among vulnerable populations.

Monoclonal antibodies targeting tumor necrosis factor-alpha (antiTNF-α) are used for patients with immuno-mediated illness as inflammatory bowel disease (IBD). However, 20-40 % of IBD patients do not respond to these therapies, and increasing knowledge of biodistribution could optimize their use and consequently their effectiveness. The aim of this study is to compare the biodistribution of adalimumab after intravenous (IV) and subcutaneous (SC) administration using Positron Emission Tomography (PET) imaging in IBD animal models. IBD was induced in mice using oral dextran sulfate sodium (DSS) and each induced animal was individually confirmed using [18F]FDG PET/CT scans, weight monitoring and histopathological analysis of colon tissue samples. The SC and IV biodistribution pharmacokinetics profiles and in vivo biodistribution of adalimumab labeled with 89Zr were evaluated using a dedicated PET/CT scanner. Mean standardized uptake values (SUV) were estimated from the colon, liver, and blood over seven days. Blood analysis revealed faster elimination of adalimumab in IBD models compared to controls, and after IV compared to SC administration (SUV 168 h p.i. SC-IBD = 0.06 ± 0.02, SC-Control = 1.08 ± 0.11, IV-IBD = 0.02 ± 0.01, IV-Control = 0.26 ± 0.13). Furthermore, IBD models exhibited faster whole-body clearance than controls and an earlier and higher concentration peak of adalimumab in the colon after IV (SUV 6 h p.i. IBD-IV = 2.11 ± 0.18) compared to SC administration (SUV 24 h p.i. IBD-SC = 1.49 ± 0.27). Our findings demonstrate the significant influence of the administration route and the TNF-α expression (local and also systemic) on the amount of adalimumab reaching the colon over time.

Patients with very early-onset inflammatory bowel disease (VEO-IBD), with an age of onset < 6 years, can present with severe manifestations and may require biologic therapy. Infliximab and adalimumab are approved for induction and maintenance in pediatric IBD patients but are licensed only above the age of 6 years. Effectiveness and safety data on adalimumab in this patient population are lacking. We assessed the therapeutic response to help close this gap.

This retrospective study involved 30 sites worldwide. Demographic, clinical, and laboratory data were collected from patients with VEO-IBD who commenced adalimumab therapy before the age of 6 years.

Seventy-eight patients (37 Crohn's disease, 26 ulcerative colitis, and 15 with IBD-unclassified) were included. Median age of IBD onset was 2.6 (1.3-4.1) years, with 30 (38.5%) patients diagnosed at age <2 years. Median age at adalimumab initiation was 4.2 (2.8-5.1) years. Adalimumab was used as second-line biologic therapy in 45 (57.7%) patients after infliximab. The median time to last follow-up was 63 (22-124) weeks. Significant improvement in clinical scores, CRP, fecal calprotectin, and weight Z-score were observed by Week 52. Adalimumab durability rates were 61.9%, 48.1%, and 35.6% after 1, 2, and 3 years, respectively. Drug discontinuation rates were not dependent on IBD type, age, prior anti-TNF exposure, or concomitant immunomodulatory treatment. Four (5.1%) patients developed serious infections, including 1 patient with TTC7A deficiency who died following adenovirus sepsis.

Adalimumab therapy is a viable therapeutic option in patients with VEO-IBD with an acceptable safety profile.

Switching from intravenous infliximab (IV-IFX) to subcutaneous biosimilar infliximab (SC-IFX) has been shown to safely maintain clinical remission and increase drug levels in patients with Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to evaluate long-term outcomes after switching from IV-IFX to SC-IFX, including the drug concentration thresholds for maintaining remission and other predictors for loss of response after the switch.

This multicenter observational study involved CD and UC patients who were in clinical remission for at least 24 weeks and were scheduled to switch from IV-IFX to SC-IFX.

Two hundred and twenty patients were included (74 UC [34%] and 146 CD [66%]). IV-IFX was administered for 52.5 months (range 25-89). Before switch, 106 (49%) patients were receiving intensified IV-IFX. While SC-IFX levels significantly increased following the switch from IV-IFX to SC-IFX, clinical parameters, C-reactive protein, and fecal calprotectin remained unchanged during follow-up. SC-IFX levels were significantly higher in patients receiving the standard IV-IFX dose than in those receiving the intensified dose. Immunomodulatory therapy at baseline and perianal disease had no effect on IFX trough levels, whereas higher body mass index was associated with increased levels. The suggested optimal SC-IFX cutoff concentration for clinical and biochemical remissions based on receiver operating characteristic analysis was 12.2 μg/mL (area under the curve [AUC]: 0.62) at Week 12 and 13.2 μg/mL (AUC: 0.57) at Week 52. Drug persistence was 92% at Week 52, with a good safety profile.

Switching from IV-IFX to SC-IFX safely maintains long-term remission in patients with CD and UC. In maintenance, the optimal cutoff point associated with remission was 12-13 μg/mL.

In contrast to previous network meta-analysis using classical frequentist methods, we evaluated the efficacy and safety of six frequently-used biologics through a Bayesian method.

Web of Science, Scopus, CENTRAL, ClinicalTrials.gov and ICTRP were searched to collect randomized controlled trials (RCTs) in adults with moderate-to-severe Crohn's disease, comparing Infliximab, Adalimumab, Certolizumab pegol, Ustekinumab, Risankizumab, or Vedolizumab, relative to placebo or an active comparator for induction of clinical response (two different definitions) and maintenance of clinical remission. A random-effects model was performed with rankings according to the surface under cumulative ranking curve (SUCRA) probability. Finally, we completed sensitivity and consistency analyses, and evaluated the certainty of evidence through GRADE working group guidance.

We identified 22 and 20 RCTs for induction and maintenance therapy, respectively. Infliximab combined with azathioprine was most effective for inducing clinical response in TNF (tumor necrosis factor) antagonist-naïve patients. For TNF antagonist-experienced patients, Ustekinumab (SUCRA 86.19) and Risankizumab (SUCRA 62.56) have the largest SUCRA in induction of clinical response. Risankizumab has the lowest risk of adverse events (SUCRA 84.81), serious adverse events (SUCRA 94.23), and serious infections (SUCRA 79.73) in induction therapy. Adalimumab and the 10 mg/kg regimen of Infliximab rank highest for maintaining clinical remission.

This analysis suggests that Infliximab in combination with azathioprine may be preferred biologic agents for induction therapy in TNF antagonist-naïve patients. For TNF antagonist-experienced patients, Ustekinumab and Risankizumab may be preferred biologic agents for induction therapy. Risankizumab potentially has the lowest safety risk worth exploring in induction therapy. Adalimumab and the 10 mg/kg regimen of Infliximab have maintenance efficacy benefits for responders to induction therapy.

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=458609, Identifier CRD42023458609.

The introduction of tumor necrosis factor inhibitors has led to a paradigm shift in the management of inflammatory bowel disease (IBD). The subsequent introduction of both anti-integrins and cytokine blockers has since expanded the biologic armamentarium. However, immunogenicity, defined as the production of anti-drug antibodies (ADAs) to the prescribed biopharmaceutical, means a significant fraction of patients exposed to biologic agents will experience a secondary loss of response to one or more of the drugs. In clinical settings, immunogenicity may be caused by several factors, both patient related (e.g., underlying chronic disease, systemic immune burden, including previous biologic therapy failure, and [epi]genetic background) and treatment related (e.g., dose and administration regimens, drug physical structure, photostability, temperature, and agitation). Here, we outline these elements in detail to enhance biopharmaceutical delivery and therapy for patients with IBD. Moreover, concurrent immunomodulator medication may reduce the risks of ADA generation, especially when using the chimeric drug infliximab. Summarizing the latest developments and knowledge in the field, this review aims to provide strategies to prevent ADA production and information on managing non-responsiveness or loss of response to biologics. Better understanding of the molecular mechanisms underlying the formation of ADAs and the critical factors influencing the immunogenicity of biopharmaceuticals may lead to improved health outcomes in the IBD community that may benefit both the individual patient and society through lower healthcare expenses.

The treatment options for chronic inflammatory bowel diseases (IBD) have been greatly expanded due to a better understanding of the underlying pathogenesis. A total of five classes of advanced treatment are available.

A practical overview of advanced treatment of IBD.

Narrative review.

Advanced treatments are indicated for moderate to severe IBD. A timely use is recommended to achieve better response rates and to avoid irreversible bowel damage. Tumor necrosis factor (TNF) inhibitors and Janus kinase (JAK) inhibitors have a broad efficacy, also for extraintestinal disease manifestations. The risk of reactivation of varicella zoster virus is increased with JAK inhibitors. In high-risk patients and an age >65 years there is possibly a moderately elevated cardiovascular risk and neoplastic side effects. The integrin alpha4beta7 inhibitor vedolizumab and the interleukin (IL) 12 and 23 inhibitor ustekinumab have very good safety profiles. Selective IL-23 inhibitors are sometimes superior to ustekinumab with comparable safety profiles with respect to efficacy. The sphingosine-1-phosphate receptor modulators ozanimod and etrasimod are approved for oral treatment of ulcerative colitis. The treatment success of the medications remains still limited and a minority of patients will not respond to every individual treatment. Thus, sequential administration of several treatments is often needed. Due to the lack of comparative studies, the personalized choice, sequence and decision for treatments are usually based on personal experience and should take patient preferences, efficacy, safety and individual patient profiles into consideration.

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. Comparator effectiveness studies between intravenous and subcutaneous administration are lacking.

Our primary outcome was to compare the effectiveness between intravenous and subcutaneous 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 1 January 2003 to 28 January 2024. Studies that compared intravenous and subcutaneous administration of the same biologic therapy in IBD patients and reported effectiveness outcomes were included. This study was registered on PROSPERO (CRD42023442675).

Twenty studies met the inclusion criteria for the systematic review. Nine vedolizumab cohort studies were meta-analysed for clinical remission and no difference was found in clinical remission rates between intravenous and subcutaneous administration (relative risk = 0.99; 95% confidence interval: 0.88, 1.11). Six infliximab cohort studies were meta-analysed for clinical remission and no difference was found in clinical remission rates between intravenous and subcutaneous administration (relative risk = 0.91; 95% confidence interval: 0.77, 1.08).

Our findings in the first meta-analysis comparing the effectiveness of intravenous and subcutaneous biologic therapies in IBD suggest there is no difference in the effectiveness between these two administration routes. However, further high-quality studies, particularly head-to-head studies are needed to confirm this finding.

Predose trough concentrations (Ctrough) of intravenous infliximab (IV-IFX) during maintenance therapy are associated with therapeutic outcomes in patients with Crohn's disease (CD). A subcutaneous formulation of infliximab (SC-IFX) has shown high Ctrough values due to its favourable pharmacokinetics.

To evaluate the association of Ctrough of SC-IFX with therapeutic outcomes and the threshold of SC-IFX Ctrough for achieving mucosal healing (MH) and transmural healing (TH) in patients with CD.

We performed this cross-sectional study in patients with CD who had received SC-IFX maintenance therapy for ≥ 6 months. We measured SC-IFX Ctrough immediately before SC-IFX injection. We performed ileocolonoscopy/single-balloon enteroscopy and/or magnetic resonance enterography within 3 months of SC-IFX Ctrough measurement. MH was defined as SES-CD-ulcerated surface subscore of 0. TH was defined as simplified MaRIA score of 0.

We enrolled 124 patients with MH in 77.9% (74/95) and TH in 36.3% (37/102). SC-IFX Ctrough was significantly higher in patients with MH (24.1 vs.16.9 μg/mL; p = 0.001) and TH (26.0 vs. 20.5 μg/mL; p = 0.007) than in those without. ROC analysis identified that the threshold of SC-IFX Ctrough for MH and TH were 17.5 and 30.3 μg/mL, respectively. Multivariate logistic regression showed that SC-IFX Ctrough was significantly associated with MH (OR 1.16; 95% CI 1.05-1.27; p = 0.002) and TH (OR 1.08; 95% CI 1.02-1.14; p = 0.005).

SC-IFX Ctrough was positively associated with MH (≥ 18 μg/mL) and TH (≥ 30 μg/mL) in patients with CD, which may guide treatment decisions to optimise therapeutic response in the era of treat-to-target.

Transition from intravenous (IV) to subcutaneous (SC) administration is an option in inflammatory bowel disease (IBD) with Infliximab (IFX) or Vedolizumab (VDZ). The aim was to compare the adherence, the persistence in therapy, and quality of life (QoL) at baseline, at 6, at 12 months of SC IFX versus SC VDZ.

This was a prospective, observational, multicenter study on patients with IBD in treatment with IV IFX or VDZ who switched to SC. All patients investigated the QoL by the short IBD Questionnaire (sIBDQ) and the concerns and expectations by a 6-item survey. Any adverse events, local and systemic, were reported. Safety, concerns, and satisfaction were evaluated.

One hundred and eight out of 93 patients were replaced, 51 to SC IFX and 42 to SC VDZ. The majority accepted the SC route. Persistence in therapy was similar between the two groups. The QoL improved after 6 months (p = 0.004), but at T12 both groups show a significant decline in QoL. SC administration has not caused any concern for patients. As safety, both groups reported a similar number of local reactions (IFX 19.60% vs VDZ 19.04%). In the IFX group were reported more systemic reactions (IFX 11.6% vs VDZ 7.14%) without the need for hospitalization.

The transition from IV to SC administration is an appropriate and safe option for treatment with IFX or VDZ. It is very important to consider the patient's choice and preference. The SC administration led to a significant benefit in QoL, especially in the first 6 months of therapy.

This American Gastroenterological Association (AGA) living guideline is intended to support practitioners in the pharmacological management of moderate-to-severe ulcerative colitis (UC).

A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to prioritize clinical questions, identify patient-centered outcomes, conduct an evidence synthesis, and develop recommendations on the pharmacological management of moderate-to-severe UC.

The AGA guideline panel made 14 recommendations. In adult outpatients with moderate-to-severe UC, the AGA recommends the use of infliximab, golimumab, vedolizumab, tofacitinib, upadacitinib, ustekinumab, ozanimod, etrasimod, risankizumab, and guselkumab, and suggests the use of adalimumab, filgotinib, and mirikizumab over no treatment. In patients who are naïve to advanced therapies, the AGA suggests using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (eg, golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication (eg, adalimumab). In patients who have previously been exposed to 1 or more advanced therapies, particularly tumor necrosis factor (TNF)-α antagonists, the AGA suggests using a higher-efficacy medication (eg, tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy medication (eg, filgotinib, mirikizumab, risankizumab, and guselkumab) rather than a lower-efficacy medication (eg, adalimumab, vedolizumab, ozanimod, and etrasimod). In adult outpatients with moderate-to-severe UC, the AGA suggests against using thiopurine monotherapy for induction of remission, but suggests using thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission. The AGA suggests against using methotrexate monotherapy, for induction or maintenance of remission. In adult outpatients with moderate-to-severe UC, the AGA suggests the use of infliximab, adalimumab, and golimumab in combination with an immunomodulator over corresponding monotherapy. However, the AGA makes no recommendation in favor of, or against, the use of non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologic alone. In patients with UC who are in corticosteroid-free clinical remission for at least 6 months on combination therapy of TNF antagonists and an immunomodulator, the AGA suggests against withdrawal of TNF antagonists, but makes no recommendation in favor of, or against, withdrawing immunomodulators. In adult outpatients with moderate-to-severe UC, who have failed 5-aminosalicylates, and have escalated to therapy with immunomodulators or advanced therapies, the AGA suggests stopping 5-aminosalicylates. Finally, in adult outpatients with moderate-severe UC, the AGA suggests early use of advanced therapies and/or immunomodulator therapy, rather than gradual step-up after failure of 5-aminosalicylates. The panel also proposed key implementation considerations for optimal use of these medications and identified several knowledge gaps and areas for future research.

This guideline provides a comprehensive, patient-centered approach to the pharmacological management of patients with moderate-to-severe UC.

Risankizumab (RZB) is a recombinant IgG1 humanized monoclonal antibody which selectively inhibits interleukin (IL)-23 though high-affinity binding of the p19 subunit. RZB was approved for use in Crohn's disease (CD) in 2022 and received regulatory approval for ulcerative colitis (UC) in the United States in June 2024.

We will examine currently available therapies for UC, provide an overview of the IL-23 pathway, discuss available trial data for RZB in UC, and comment on how RZB may fit into the current UC treatment paradigm and future directions in the field.

RZB appears to be an effective agent for inducing and maintaining remission in patients with both treatment-naïve and refractory UC, with a favorable safety profile. The selective blockade of IL-23 has demonstrated potential advantages in efficacy over combined IL-12/23 inhibition for other disease states like CD and psoriasis, although where it will be positioned amidst other clinically available advanced therapies in UC requires further study.

In the treatment of inflammatory bowel disease (IBD), we have biologic therapies administered intravenously and subcutaneously. Recently, some drugs can be administered by either of these routes. The real impact that intravenous administration has on the perception of the disease and the personal and work life of the patient is unknown.

All IBD patients receiving intravenous infliximab treatment for at least 6 months were anonymously invited to participate. They were provided with a specific structured questionnaire with visual analogue scales (0-10) at two reference centers in the Barcelona area.

A total of 90 patients with a median age of 45 years (36-56) and a median infliximab treatment duration of 48 months (24-84) were included. The visit and therapy with infliximab in the day hospital were globally well evaluated (9, IQR 7-10). 78% of patients combined day hospital stays with other activities (26% employment). The personal impact was generally low (4, IQR 0-5.8), but the patient's job was threatened in 43% of patients on intensified treatment.

The intravenous administration of biologic drugs on an outpatient basis is highly satisfactory among IBD patients. The impact on the work sphere appears to be more pronounced than on the personal sphere, an aspect that should be considered in shared decision-making with the patient.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by growing incidence and prevalence around the world in the last few decades. The range of available existing treatment and strategies for its management is being implemented. Given the introduction of newly developed molecules and the lack of specific guidelines, drug positioning may represent a tough clinical challenge. UC management is mostly medical, and it has been shifting toward a more personalized approach with the aim to create a tailored strategy depending on the patient's profile. A treat-to target strategy seems to be the best approach to reach disease control as it allows to carry out therapeutic choices based on objective and specific parameters: histological, ultrasonographic, and molecular targets may add to the already used clinical, endoscopic, and biochemical targets. In addition, dual-targeted therapy has emerged as an attractive therapeutic strategy for patients not achieving remission. This review aims to provide an overview of the available strategies to raise the bar in UC.

Since 2015, an infliximab biosimilar, CT-P13, has been approved for commercial use in many countries, easing the economic burden borne by society and patients. Many clinical trials investigating CT-P13 for the treatment of IBD have been conducted and reported that it may be a substitute for infliximab. However, the differences between the efficacy of CT-P13 and infliximab-originator require further elucidation.

Data on the rates of clinical response, clinical remission, and mucosal healing of IBD were pooled for random-effects model meta-analysis using Stata MP 17. A total of 30 studies were included.

The pooled risk of clinical remission rate of patients with Crohn's disease and ulcerative colitis who were naïve to biologics at 08-14 weeks were 0.66 (95% CI, 0.58-0.75) and 0.48 (95% CI, 0.43-0.54), respectively, and at 100-104 weeks were 0.66 (95% CI, 0.49 to 0.84) and 0.71 (95% CI, 0.62 to 0.79) respectively. The pooled risk of clinical remission rate of patients with Crohn's disease and ulcerative colitis who were transitioned from the original agent at 24-32 weeks were 0.84 (95% CI, 0.77-0.92) and 0.78 (95% CI, 0.63-0.93), respectively, and at 48-54 weeks were 0.72 (95% CI, 0.62 to 0.82) and 0.78 (95% CI, 0.71 to 0.86) respectively. The pooled rates for mucosal healing in ulcerative colitis were 0.56 (95% CI: 0.46 to 0.67) at 08-14 weeks, and 0.64 (95% CI: 0.42 to 0.85) at 48-54 weeks. RCT studies showed no significant change in efficacy after switching, whether Crohn's disease or ulcerative colitis.

CT-P13 is effective in short and long-term periods. The application of CT-P13 for the management of IBD was promising.

The Saudi Food and Drug Authority (SFDA) has approved the subcutaneous (SC) administration of infliximab, presenting a more convenient alternative with reduced outpatient visits and diminished expenses compared to the intravenous (IV) administration. However, the financial implications of this formulation have not been examined from the perspective of Saudi payers.

A prevalence-based budget impact model was developed to evaluate the financial effects of introducing "environment without" versus "with infliximab SC." The model's time horizon spanned over 2 years (2021-2023), aligning with the biennial national pharmaceutical procurement cycle. The comparison focused on infliximab SC versus all available formulations of infliximab IV in the Saudi market for two inflammatory bowel diseases (IBD): Ulcerative Colitis (UC) and Crohn's Disease (CD). Treatment comparators' comparability and dose escalations were substantiated by published studies, utilizing dosing information from the summary of product characteristics. Drug acquisition costs were derived from SFDA registered prices, with IV formulation administration costs included. Scenario analysis assessed the budget impact of infliximab SC introduction at uptake rates ranging from 0% to 100%.

Introducing infliximab SC demonstrated cost-saving potential in the treatment of IBD. At 100% uptake with UC patients for 2 years, infliximab SC resulted in savings of -SAR-31.9 million (-SAR29,145 per patient). Similarly, for CD, introducing infliximab SC at 100% uptake over 2 years yielded savings of -SAR106.2 million (-SAR36,585 per patient).

This study reveals that infliximab SC is associated with cost-saving potential when compared to infliximab IV formulations available in Saudi Arabia. Future research should address uncertainties related to real-world comparative effectiveness, the convenience of administration, patient tolerability, and physician acceptance of the SC formulation of infliximab, alongside comparisons with other TNF-alpha inhibitors.

Subcutaneous (SC) formulations of infliximab (IFX) and vedolizumab (VDZ) are approved for the treatment of inflammatory bowel diseases (IBDs). Our aim was to evaluate the effectiveness of switching from intravenous (IV) to SC formulations of IFX and VDZ in IBDs.

This multicentre, retrospective study collected data of adult patients with Crohn's disease (CD) or ulcerative colitis (UC) switched to SC IFX or VDZ. The primary endpoint was clinical remission at 12 months stratified based on timing of switch. A composite endpoint consisting of therapy discontinuation, reverse-switch, need for steroids, and drug optimization was evaluated. A multivariate analysis investigated the association between patients' characteristics and outcomes.

Two hundred and thirty-one patients (59% UC, 53% male, mean age 44 ± 15 years, 68% IFX) from 13 centres were included. The switch occurred at Week 6 in a third of cases (36%). Median time to switch was 13 months. Most patients switched to SC IFX and VDZ were in clinical remission at 3 (87% and 77%), 6 (86% and 83%) and 12 (63% and 60%) months. In the multivariate analysis, there was no difference in clinical remission rate at 12 months; however, patients switched at Week 6 had a higher rate of experiencing any therapeutic changes at 3 (false discovery rate (FDR) = .002), 6 (FDR <1 × 10-10) or 12 months (FDR = .08). Clinical disease activity at baseline (only in UC) (FDR = .07) and previous exposure to biologics (FDR = .001) were risk factors for composite endpoint at 6 and 12 months.

SC IFX and VDZ are effective in daily clinical practice in IBD patients. Switching patients in remission reduces the risk of negative outcomes.