Introduction

Transmural healing (TH) is a relevant target of biologic therapy in Crohn's disease (CD). Despite stable clinical remission, a proportion of patients (pts) under long term anti-TNF shows an increased bowel wall thickening (BWT). The causes of this are not clear.

Aims & Methods

This study aims to determine factors correlated with failure to reach TH despite long standing clinical remission with anti-TNF in CD.
This prospective study recruited a consecutive series of CD patients under adalimumab (ADA) or infliximab (IFX) in clinical remission since ≥1 year. Patients without clinical and sonographic assessment or increased BWT when starting biologic therapy, were excluded.
At enrollment the following parameters were collected: BMI, smoking, age at diagnosis, duration of CD, CD behavior and location, previous surgery, duration of clinical remission, previous use and duration of anti-TNF therapy, and concomitant immunomodulators. All pts underwent therapeutic drug monitoring (TDM) of ADA or IFX trough serum levels and intestinal ultrasound (IUS). TDM were assessed using a commercial assay, using therapeutic TL concentration >5mg/mL for IFX, and >7.5ug/mL for ADA and results were grouped as inferior to, up to thrice and more than thrice the normal value. IUS assessments, including those at the start of therapy, were performed by 2 expert sonographers (>10000 IUS). BWT at IUS was classified as: transmural healing (TH, BWT ≤3mm), transmural response (TR, BWT<25% of baseline) and no response (NR, BWT>4.5mm and no TR). Univariate analysis was performed and variables with p<0.3 entered a multivariate binary logistic regression analysis to identify those independently associated with the outcomes of interest (TH, TR, NR).

Results

68 pts were included, 49 men with mean age of 32.2yrs, mean disease duration of 12.4yrs and remission duration of 4.1yrs. 18 pts were on IFX and 50 ADA, with a mean duration of therapy of 3.6 yrs. 36 pts (52.9%) showed anti-TNF TL below the normal threshold. 22 pts (38.4%) showed TH, 32 (47.1%) TR and 26 (38.2%) no response to treatment.
TH correlated with inflammatory CD phenotype (p 0.002), duration of remission (p 0.01), high TL of ADA (p 0.02), lower baseline BWT (0.0005) and absence of strictures at IUS after therapy (p 0.03). At multivariate analysis TH significantly correlated with BMI (p 0.01) and lower baseline BWT (CI95% -1.12 -0.1, p 0.01).
TR correlated with inflammatory phenotype (p 0.01), higher serum TL of ADA (p 0.001) and IFX (p 0.04) and overall with higher drug levels (p 0.01) and absence of strictures after therapy (p 0.04). At multivariate analysis TR correlated with shorter CD duration (CI95% -1.75 -0.13, p 0.02), higher drug levels (CI95% 0.03 0.22, p 0.01) and non stricturing phenotype (CI95% -2.85 -0.31, p 0.01)
NR was correlated with stricturing phenotype (p 0.007), lower serum TL of ADA (p 0.005) and IFX (p 0.04) and overall with lower levels of anti-TNF (p 0.005), greater baseline BWT (p 0.001) and stricture after therapy (p 0.002). At multivariate analysis NR correlated with lower BMI (CI95% -0.52 -0.09, p 0.004), lower drug levels (CI95% -0.32 -0.04, p 0.01), higher BWT at baseline (CI95% 0.11 1.21, p 0.02) and stricturing phenotype (CI95% 1.16 5.27, p 0.002).

Conclusion

Persistence of increased BWT in CD patients in stable clinical remission under biologic therapy is multifactorial and seems mainly due to sub-therapeutic TL of anti-TNF and development of strictures. High BWT when starting treatment, low BMI, development of strictures during treatment, disease duration and lower TL of anti-TNF alpha are key factors of the behavior of BWT and in reaching TH.

Disclosure

None

Introduction

Transmural healing is a promising target in Crohns’ disease (CD) that is associated with more favorable outcomes than endoscopic remission, especially lower risk of bowel damage progression. C-score has been recently developed and validated to assess transmural healing in patients with CD. However, the best time to assess transmural healing remains to be determined.

Aims & Methods

We aimed to evaluate the kinetics of transmural healing in patients with CD treated with anti-TNF therapy.
From a prospective database of patients with CD performing MRI for luminal CD, we analyzed the kinetics of transmural healing among CD patients older than 18 years-old receiving anti-TNF therapy, with objective sign of inflammation on morphological evaluation (cross-sectional imaging) before starting the treatment, who underwent at least one MRI examination to assess therapeutic efficacy within 12 months. Patients treated with anti-TNF agents for treat isolated perianal lesions were excluded.
We used a statistical model based on imputation according the last observation carry forward and clinical relevance. Transmural healing was then assessed every month during the first year. For segmental analysis, we used the same division into segments than recommended for Lemann Index calculation. Transmural healing was defined as C-score < 0.5 in each segment. C-score was calculated as previously published (0.2 x (bowel thickness in mm – 3) + 2 if ulcer + 1.5 if enlarged lymph nodes).

Results

Overall, 123 patients were included. Among them, 90 were female (73.1%), 48 (39.9%) were current smokers and 53 (43.0%) had prior intestinal resection. The median CD duration at baseline was 7.6 years [1.4-15.2]. At baseline, 41 patients (33.3%) were anti-TNF-naïve. At baseline, 67 patients (55.3%), 53 patients (43.8%) and 1 patient (0.8%) were treated with infliximab, adalimumab and golimumab, respectively with concomitant immunosuppressant in 94 patients (79.0%).
At baseline, 220 segments were considered as active (C-score > 0.5) including 100 in the terminal ileum and 120 in the colon/rectum.
According per-segment analysis (N=220), the rate of transmural healing was 6.4% at M1, 6.4% at M2, 10.0% at M3, 10.1% at M4, 14.6% at M5, 18.0% at M6, 23.2% at M7, 24.5% at M8, 26.0% at M9, 26.8% at M10, 29.1% at M11 and 30.4% at M12.
Among terminal ileum segments (n=100), the rate of transmural healing was 2.0% at M1, 2.0% at M2, 5.0% at M3, 5.0% at M4, 9.0% at M5, 12.9% at M6, 16.0% at M7, 17.0% at M8, 18.0% at M9, 19.0% at M10, 20.0% at M11 and 20.0% at M12.
Among colorectal segments (n=120), the rate of transmural healing was 6.4% at M1, 6.4% at M2, 13.8% at M3, 13.8% at M4, 15.6% at M5, 22.0% at M6, 28.4% at M7, 28.6% at M8, 28.6% at M9, 28.6% at M10, 32.8% at M11 and 34.4% at M12.
Among the 123 patients with CD, in multivariable analyses, absence of transmural healing (C-score > 0.5) within the first year was associated with increased risk of surgery (HR=3.37 [1.30-8.68]; p=0.012), drug discontinuation (HR=2.31 [1.29-4.14]; p=0.005), and bowel damage progression (p <0.001) while we observed a trend for higher risk of CD-related hospitalization (HR=1.92 [0.85-4.36]; p=0.11).

Conclusion

Transmural healing is achievable in more than 30.0% of active segments in patients with CD treated with anti-TNF therapy within the first year. The best time to assess transmural healing was between 6 and 12 months after starting anti-TNF therapy with higher rate of transmural healing for colorectal versus ileal segments. Transmural healing defined as C-score < 0.5 is associated with long-term improved outcomes in patients with CD.

Disclosure

Consulting fees from: Abbvie, Amgen, Arena, Biocon, Biogen, Celltrion Healthcare, CTMA, Ferring, Galapagos/AlfaSigma, GutyCare/Resilience Janssen, Lilly, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda et Tillotts
Lecture fees from: Abbvie, Amgen, Biogen, Celltrion Healthcare Galapagos/AlfaSigma, Ferring, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma
Research grants/fundings from: Abbvie, Celltrion Healthcare, Janssen, Lessaffre, Lilly, Pfizer, Sandoz and Takeda

Introduction

Advances in therapeutic drug monitoring (TDM) have significantly improved the understanding of the relationship between anti-TNF-alpha drug concentrations and disease activity in patients with Crohn’s disease (CD). Early dose optimization of adalimumab (ADAL) and higher serum trough concentrations are associated with increased clinical, biochemical, and endoscopic remission in CD^1,2,3,4. This study aimed to evaluate whether early dose optimization of ADAL to a trough level >15 µg/mL improves clinical and biochemical remission rates at 12 weeks compared to standard dosing.

Aims & Methods

This study aimed to evaluate whether early dose optimization of ADAL to a trough level >15 µg/mL improves clinical and biochemical remission rates at 12 weeks compared to standard dosing. This was a randomized, multicenter, open-label trial evaluating TDM-guided ADAL dose optimization versus standard dosing in biologic-naïve and experienced patients with active CD. In the dose optimization arm , after standard induction doses at Weeks 0 (160 mg) and 2 (80 mg), patients with trough levels ≤15 µg/mL at week 4 received an additional 80 mg at Week 6 followed by 40 mg every week. Patients in the optimization arm who had trough levels >15 µg/mL at week 4 and all patients in the standard care arm remained on 40 mg every 2 weeks. The primary endpoint was a composite of clinical and biochemical remission at Week 12, defined as Harvey-Bradshaw Index (HBI) <5 and C-reactive protein (CRP) <5 mg/L or fecal calprotectin (FCal) <250 µg/g.

Results

A total of 77 patients were enrolled in the trial (39 in optimization arm vs 38 in standard care arm). At week 4, 15/39 patients in the intervention arm were eligible for dose optimization, with twelve going on to receive the accelerated regimen. At week 12, 6/12 (50%) of the optimized patients achieved an ADAL trough level >15 µg/mL. A numerically higher proportion of patients in the dose optimization arm achieved the primary endpoint compared to the standard care arm, however this difference was not statistically significant (17 (43.6%) vs 12 (31.6%), p = 0.394). In total, eleven patients in the optimization arm (28.2%) and seven patients in the standard care arm (18.4%) achieved an ADAL trough >15 µg/mL, with mean trough levels being numerically higher in the optimization group (18.1 vs 12.8 µg/mL, p = 0.160). ROC analysis of the predictive value of Week 12 trough levels on the primary outcome determined an optimal threshold level of 18.2 µg/mL (AUC 0.68, sensitivity 88.9%, specificity 39.3%). When analyzing the entire cohort, patients who achieved an ADAL trough >15 µg/mL (whether they were dose-optimized or not) at Weeks 8 or 12 were significantly more likely to achieve combined clinical and biochemical remission (19/27 patients (70.4%) vs 10/50 patients (20.0%), p < 0.001). Taken separately, both clinical and biochemical remission occurred more frequently in patients who achieved an ADAL trough >15 µg/mL (clinical: 22/27 (81.5%) vs 16/50 (32.0%), p <0.001; biochemical: 22/27 (81.5%) vs 14/50 (28.0%), p < 0.001). No difference in adverse effects was observed between trial arms. The major limitation of the trial was the small sample size and patient withdrawal due to the COVID 19 pandemic.

Conclusion

Although proactive dose optimization did not significantly increase remission rates compared to standard dosing, achieving an ADAL trough level >15 µg/mL at Week 8 or 12 was strongly associated with higher remission rates. These findings support early TDM-driven dose escalation and suggest that maintaining ADAL >15 µg/mL is a key target for achieving biochemical remission.

References

1. Little RD, Swaine A, Reynolds R, et al. Adalimumab Drug Levels at Secondary Loss of Response Do Not Predict Response to Dose-intensification in Crohn’s Disease: A Retrospective, International Multicenter Study. Inflamm Bowel Dis. 2024;30(10):1714-1723. doi:10.1093/ibd/izad248
2. Assa A, Matar M, Turner D, 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.e2. doi:10.1053/j.gastro.2019.06.003
3. Chaparro M, Guerra I, Iborra M, et al. 538 Correlation Between Adalimumab Serum Levels and Remission After the Induction Phase in Crohn’s Disease Patients. Gastroenterology. 2015;148(4):S-107-S-108. doi:10.1016/S0016-5085(15)30370-X
4. Kim MJ, Kim E, Kang B, Choe YH. Therapeutic Drug Monitoring of Adalimumab During Long‐term Follow‐up in Paediatric Patients With Crohn Disease. J Pediatr Gastroenterol Nutr. 2021;72(6):870-876. doi:10.1097/MPG.0000000000003070

Introduction

In recent years, magnetic resonance enterography (MRE) has emerged as a novel tool for assessing disease activity in patients with Crohn’s disease (CD). It is well known that anti-TNF agent trough levels (TLs) are associated with endoscopic healing (EH) in CD. However, limited data exist regarding the correlation between transmural healing (TH) and TLs in CD.

Aims & Methods

​​​​​​This study aimed to evaluate the correlation between anti-TNF TLs and TH, as well as mucosal healing (MH). We conducted a single-center cross-sectional study including CD patients on maintenance therapy with infliximab (IFX) or adalimumab (ADA) for at least one year. All patients underwent ileocolonoscopy and MRE at baseline and between one and two years after initiating anti-TNF therapy. TH was assessed using the simplified Magnetic Resonance Index of Activity (MARIAs) and was defined as the absence of inflammatory signs in the terminal ileum and all colonic segments. IFX and ADA TLs were measured using the Quantum Blue® assay (BÜHLMANN, Schönenbuch, Switzerland). EH was defined as a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of <3 points on colonoscopy. The correlation between IFX or ADA TLs, TH, and MH was analyzed using receiver operating characteristic (ROC) curve analysis.

Results

A total of 52 consecutive patients with active CD were included (55.8% male; median age, 37.04±15.49 years). Among them, 37 (71.15%) were on IFX and 15 (28.85%) on ADA. The mean TL values were 7 mg/dL for IFX and 15 mg/dL for ADA. An improvement in the MARIAs score after initiating anti-TNF therapy was observed in 54% of cases (p=0.02), regardless of the biologic agent used. Regarding SES-CD, an average decrease of 85% for ADA (p<0.01) and 82% for IFX (p<0.01) was observed.
Mean TL values >2.25 mg/dL for IFX and >14.45 mg/dL for ADA were associated with TH according to the MARIAs score; however, the correlation was weak [AUC: 0.6 (0.43–0.77)]

Conclusion

Satisfactory trough levels of IFX and ADA were associated with a significant decrease in MARIAs and SES-CD scores. However, no clear correlation between TLs and TH was demonstrated. Further studies investigating long-term TH and proactive dosing strategies based on therapeutic drug monitoring may help clarify whether an association between anti-TNF TLs and TH exists.

Introduction

Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Current therapies include monoclonal antibodies, such as adalimumab (ADA) and infliximab (IFX), that target the inflammatory cytokine tumor necrosis factor alpha, collectively known as anti-TNF. While it has been shown that anti-TNF is effective at inducing and maintaining remission in patients with CD, this treatment fails in up to 40% of CD patients^​. Ineffective treatment results in disease progression and complications, emphasizing the need to understand mechanisms behind non-response and to define prognostic biomarkers. We previously identified differences in the peripheral blood DNA methylome associated with response and non-response. However, it is unclear how differential methylation can affect the transcriptome.

Aims & Methods

In this study, we assembled a cohort of 58 adult CD patients that were scheduled to start ADA or IFX treatment. Response to treatment was assessed after 6-9 months based on strict combination of endoscopic (≥50% reduction SES-CD), biochemical (CRP reduction ≥50% or CRP≤5 mg/L and FCP reduction ≥50% or FCP ≤250 µg/g) and clinical criteria (≥3 point drop in HBI or HBI ≤4 without corticosteroids). Whole peripheral blood leukocytes (PBL) were collected from patients before baseline endoscopy or at first infusion/injection, and 6-9 months later. mRNA was extracted using QIAsymphony system, converted into cDNA and sequenced in a paired-end format on the Illumina NovaSeq at the Amsterdam UMC Core Facility Genomics. Differential expression (DE) analysis was carried out within the R statistical environment (v 4.3.1) using the Bioconductor package DESeq2 (v 1.40.2).

Results

Prior to the start of treatment, we identified 504 and 750 differentially expressed genes (DEGs) distinguishing responders from non-responders in ADA and IFX cohorts, respectively. While 13 genes presented response-associated differential expression for both ADA and IFX, no overall correlation was observed between response-associated differential expression profiles. However, based on canonical pathway analysis, we found that expression differed in both ADA and IFX responders and non-responders at the level of neutrophil degranulation, B-cell receptor regulation, and cell growth and differentiation.

Conclusion

Our data suggest that response to ADA and IFX can be associated to the PBL transcriptome prior to treatment. Furthermore, while the differences between responders and non-responders to ADA and IFX display limited overlap in DEGs, we observe that response-associated pathways are shared.

Introduction

The treatment of Crohn’s disease remains a complex challenge, with approximately 20% of patients not responding to conventional therapies. Among the available options, biologic therapies particularly tumor necrosis factor (TNF) inhibitors play a key role. This study aims to describe the epidemiological, clinical, and therapeutic characteristics of patients with Crohn’s disease treated with anti-TNF agents, and to compare their efficacy.

Aims & Methods

This is a retrospective, descriptive, comparative, and analytical single-center study conducted in a gastroenterology department over a 20-year period (2004–2024). It included patients with Crohn’s disease treated with anti-TNF biologics. Data were collected from patient medical records and follow-up consultations. We analyzed epidemiological, clinical, paraclinical, therapeutic, and disease progression parameters, and compared the efficacy of infliximab and adalimumab.

Results

Out of 1,200 patients followed for Crohn’s disease, 20.3% (244) received anti-TNF therapy (adalimumab or infliximab). The mean age at diagnosis was 33.5 ± 14.3 years, with a male-to-female ratio of 1.3. Smoking was reported in 16.9% (40) of cases. The median diagnostic delay was 1 year [0–3], and the median disease duration was 4 years [1–9]. Extraintestinal manifestations were found in 37.4% (91) of patients. According to the Montreal classification, ileocolonic (L3) involvement was most common (49.6%), followed by colonic (L2, 24%), ileal (L1, 18.2%), and upper GI tract involvement (L4, 8.3%). The inflammatory phenotype was observed in 46.7%, stricturing in 27.7%, fistulizing in 17.8%, and both stricturing and fistulizing in 7.9% of patients. Perianal disease was associated in 45.9% (111) of cases.
Regarding baseline laboratory parameters: hemoglobin ≤10 g/dL was found in 35.3% (48), white blood cell count <8000/μL in 64.7% (88), platelet count >150,000/μL in 97.7% (125), CRP >6 mg/L in 83.4% (121), and albumin <30 g/L in 31.5% (40) of patients.
Therapeutically, 55% (134) of patients had undergone surgery. Corticosteroids were used in 56.6% (137) before initiating anti-TNF therapy, and 66.4% (166) received combination therapy. The overall remission rate at 54 weeks was 74.6% (179). Infliximab was prescribed in 74.9% (182) and adalimumab in 25.1% (61) of cases, with comparable efficacy: 76.3% (45) remission with adalimumab versus 74% (134) with infliximab (p = 0.732), showing no statistically significant difference.

Conclusion

Anti-TNF therapies currently play a major role in the management of moderate to severe Crohn’s disease. In our study, both infliximab and adalimumab showed satisfactory clinical, biological, and endoscopic responses at 54 weeks, with no statistically significant difference