Introduction

Side effects, patient preference, and high costs may prompt cessation of anti-TNF therapy in ulcerative colitis (UC) patients in sustained remission. Given the risk of relapse, careful patient selection is essential. This study aimed to assess relapse rates and identify predictors of relapse following anti-TNF cessation in UC patients in remission.

Aims & Methods

A systematic search on cohort studies reporting relapse rates after cessation of anti-TNF therapy in ≥30 UC patients in clinical remission was performed 6 September 2024. Individual patient data was requested. We excluded patients with steroid use, ≤6 months anti-TNF therapy, ≤16 years, previous colectomy (n=4), golimumab as anti-TNF therapy (n=3) or without follow-up. Continuation of treatment with immunomodulators or mesalamine at cessation of anti-TNF was allowed. Relapse was defined as the need to (re)start treatment with steroids, anti-TNF or other advanced therapies, or the need for surgical treatment, as applied by the original author. Pooled relapse rates were computed using a random-effects model. A prediction model was built with a Cox proportional hazards model, performance assessed by iteratively leaving one study out (internal-external cross-validation, IECV). Missing covariate data were multiply imputed 100 times using the MICE algorithm. Variable selection was guided by three criteria: ≤20% missing data, a univariate p-value ≤ 0.2, and input from clinical experts.

Results

In total, 654 patients from 8 studies were included in the individual participant data meta-analysis. At anti-TNF cessation, median age was 40 years (IQR 31-51) with a median anti-TNF treatment of 18 months (IQR 18-36). The majority of patients were treated with infliximab (n = 610, 93%). Only 42 patients (9%) received a second-line anti-TNF therapy. The pooled relapse rate were 24% [95% CI 19-29%, I² = 44%] and 34% [95% CI 29-40%, I² = 39] at 1 and 2 years after cessation, respectively. Upon cessation, 211 patients (33%) continued mesalamine, 239 (39%) thiopurines, and 136 (22%) a combination of both. In our model, thiopurine therapy and older age at cessation were associated with a reduced risk of relapse, whereas immunomodulator refractoriness as an indication for starting anti-TNF therapy was associated with an increased risk. Other factors included in the prediction model were disease extent, type of anti-TNF therapy, history of anti-TNF therapy, fecal calprotectin level and endoscopic activity, leading to a c statistic of 0.55 [95% CI 0.51-0.59] (Table 1).

Table 1: Predictors of relapse in a pooled Cox regression analysis

Conclusion

Approximately 1 in 4 patients experience a relapse of UC within 1 year after anti-TNF cessation, increasing to 1 in 3 within 2 years. Continuation of thiopurines is associated with a reduced risk. A prediction model for relapse was developed in this large IPD meta-analysis cohort and may aid in shared decision-making on anti-TNF cessation. However, its limited discriminative ability underscores the need for further refinement, incorporating data on microscopic remission and molecular and immunological markers to better capture deeper disease control.

Introduction

Management of perianal fistulas in Crohn’s disease (CD) is challenging and requires a multidisciplinary approach, combining surgical drainage and biologic therapies, such as infliximab (IFX). Higher IFX trough concentrations have been associated with improved fistula healing rates. The subcutaneous (SC) formulation of IFX achieves 2–3 times higher and more stable trough levels compared to intravenous (IV) formulation. This study hypothesizes that SC IFX could enhance perianal fistula healing rates in CD patients.

Aims & Methods

REMSILAP study is part of the 3TLAP cohort, a French prospective multicenter observational study evaluating optimal therapeutic strategies for achieving clinical and radiological remission of perianal fistulas in CD at 12 months post-surgical drainage. The REMSILAP substudy focuses specifically on patients receiving SC IFX. Patients who received SC IFX after or within six months prior to surgical drainage were included. Baseline was defined as the day of surgical drainage. The primary outcome was the proportion of patients achieving complete clinical remission defined as Perianal Disease Activity Index (PDAI) fistula drainage subscore = 0 associated with PDAI activity restriction subscore <3 and absence of seton, and radiological remission at 12 months. Here, we present preliminary findings from REMSILAP.

Results

Among the 353 patients enrolled in the 3TLAP cohort, 54 were included in REMSILAP. The cohort consisted of 61.1% male patients, with a median age of 36 years and a median disease duration of 4.5 years. Penetrating disease (B3 phenotype) was present in 40.7%, and 33.3% had a history of surgical resection. At baseline, 40.7% of patients had quiescent disease regarding Harvey-Bradshaw index, while 5.6% had severe disease activity. Biologic exposure prior to inclusion was noted in 42.6%. Surgical drainage, with seton placement, was performed in 74.1% of patients. Forty-eight patients (88%) initiated SC IFX treatment after surgical drainage. Of the patients receiving SC IFX, 50% transitioned to SC IFX after less than three IV infusions. Among those on IV IFX at baseline, 20.4% were receiving a 10 mg/kg dose. Forty-three patients (79.6%) received SC IFX in combination with immunomodulators (azathioprine, methotrexate, or 6-mercaptopurine). The median duration of SC IFX treatment was 13.1 months, with treatment maintained for 67.5% of the follow-up period (mean: 19.3 ± 11.3 months). Forty-three patients (79.6%) were treated with a stable dose of 120 mg/14 days and 6 patients (11.1%) had an intensification of SC IFX dosage to 120mg / 7 days. At 12 months, 42 patients were evaluable for clinical outcomes. Complete clinical healing at 12 months was achieved in 11 patients (27.5%) and association of PDAI restriction subscore <3 and drainage subscore = 0 was found in 18 patients (42.9%). Thirteen patients (34.2%) from the 25 patients who had received at least 6 months of SC IFX treatment showed clinical healing at 6 months. Out of the 26 patients treated with at least 12 months of SC IFX treatment, clinical healing was achieved in 16 patients (61.5%) at 12 months. Among the 11 patients with clinical healing at 12 months, 8 (72.2%) were treated with SC IFX treatment following more than three IFX IV infusions. None of the 11 patients with available MRI date showed radiological healing at 12 months.

Conclusion

Subcutaneous infliximab following surgical drainage of Crohn’s disease perianal fistula demonstrates high treatment persistence and promising rates of fistula healing.

Disclosure

This study was funded by Celltrion Healthcare France

Introduction

Treatment response in inflammatory bowel disease (IBD) is highly variable, with an urgent need for biomarkers to guide therapeutic decisions. Circulating monocytes, key players in intestinal immunity, act as precursors to tissue macrophages and contribute to inflammation and mucosal healing. The transcriptional programs that govern monocyte fate and their association with treatment outcomes remain poorly defined. Ikaros family proteins regulate gene expression through distinct mechanisms in lymphocytes, but little is known about their role in monocyte-macrophage function in IBD. We aimed to investigate the role of Ikaros family (Ikaros, Helios, Aiolos, Eos, Pegasus) in shaping monocyte function linked to advanced therapies response.

Aims & Methods

Peripheral blood samples were collected at baseline (W0) and after 8-12 weeks of induction therapy (W8/12) from IBD patients who initiated or switched advanced therapy [biologics, oral synthetics] and from healthy controls (HC) (n=8). We included patients achieving clinical remission after induction [Super-Responders] SR (n=18) and those showing no response [Non-Responders] NR (n=16). Immune phenotype and expression of Ikaros proteins were assessed via multiparametric flow cytometry (FACS) and correlated with clinical outcomes. To assess functional roles of Ikaros proteins, monocyte-derived macrophages were generated in vitro from buffy coat (n=6). Cells were polarised using cytokine cocktails to induce pro-inflammatory (LPS+IFNγ or TNF+PGE2+Pam3CSK4; TPP), alternative (IL1β+LPS), or regulatory (IL10) phenotypes. siRNA-loaded nanoparticles were used to silence Ikaros or Helios prior to polarisation. Phenotypic changes were analysed by FACS; cytokines secretion by ELISA; genes expression by qPCR; and phagocytosis by fluorescent beads uptake.

Results

At W0, IBD patients exhibited a significant increase in circulating monocyte counts (vs HC, p<0.001). At W8/12, monocyte levels significantly decreased in the SR group, while remaining elevated in the NR group. FACS analysis revealed an increased proportion of non-classical monocytes (CD14⁻CD16⁺) in the IBD group at W0 (vs HC; p< 0.05), persisting in NR at W8/12 (vs SR; p<0.05). IBD monocytes also showed higher expression of CCR2 and CX3CR1 compared to HC. Helios expression was absent in monocytes from IBD patients at W0, while the mean expression of Helios was 47.31% in monocytes from the HC group. At W8/12, Helios expression re-emerged in 34.14% of monocytes derived from the SR patients but remained undetectable in the NR. In vitro, macrophages treated with LPS+IFNγ or TPP upregulated Ikaros, STAT1, and CXCL10 gene expression (p< 0.01), while Helios, TGM2, and MCR1 were upregulated in response to IL10 (p< 0.05). Helios expression was absent in TNF-stimulated macrophages. Ikaros silencing reduced pro-inflammatory markers, IL6 and IL1β cytokines secretion, and inhibited phagocytosis in response to LPS, whereas Helios silencing increased macrophages activation, and pro-inflammatory markers in response to IL10.

Conclusion

Monocyte subsets distribution and Helios, Ikaros expression dynamics clearly distinguished SR from NR in IBD. Sustained absence of Helios and persistence of non-classical monocytes in NR suggest a failure to transition toward a regulatory phenotype. This may further contribute to altered migratory capacity and influence their functional fate within intestinal tissue. Functional assays confirm opposing roles of Ikaros and Helios in the macrophages activation, underscoring their unique potential as biomarkers or therapeutic targets to modulate inflammation in IBD.