Introduction

Crohn's disease (CD) is a disabling and destructive disease. Early intervention associated with tight monitoring appear to the best way to achieve deep remission and to prevent disease progression. Whether anti-TNF (tumor necrosis factor) therapy can be interrupted in patients with early CD who have undergone a period of prolonged deep remission is unknown.

Aims & Methods

The primary objective was to evaluate the sustained deep remission rate one year after discontinuation of a 12-month course of adalimumab in adult patients with early CD who achieved deep remission at 12 months after treatment induction and who were already in clinical remission and biomarker remission at 6 months.
We carried out a multicentre prospective GETAID cohort study. All patients had early luminal CD less than 24 months since diagnosis, and were naïve to biologics. The primary study endpoint was percentage of patients with sustained deep remission one year after stopping a 12-months course of adalimumab (+/- 3 months) in adult patients with early-stage CD who achieved deep remission without therapeutic intervention (i.e. no surgery, no clinical flare-up, no introduction of CD-related treatment, no need for adalimumab optimization) AND who were already in clinical remission (CDAI < 150) and biomarker remission (CRP < 5 mg/L and fecal calprotectin < 250) at 6 months. A clinical flare-up was defined as a CDAI > 220 or an increase in CDAI between two subsequent visits > 70.

Results

A total of 171 patients received treatment with adalimumab between March 2015 and March 2019.
In this cohort, 39.2% (67/171) were active smokers. The median disease duration was 4 [2-9] months. CD location was ileal (42.7%, 73/171), colonic (12.3%, 21/171), and ileo colonic (44.4%, 76/171). Twenty-one patients (12.3%) had perianal disease. The majority of patients had an inflammatory phenotype (71.3%, 122/171). At inclusion, median CRP level was 9.0 [3.0-24.0] mg/L, and median fecal calprotectin was 440.5 [159.0-838.0] µg/g.
Overall, 38/171 (22.2%) of patients achieved deep remission after a 12-month course of adalimumab. From those who achieved deep remission, 7 patients did not discontinue adalimumab. In this study, 7/31 (22.6%) patients maintained their deep remission for one year after their treatment discontinuation (24 months from initiation of adalimumab). Among the whole cohort, only 4% (7/171) of patients were in deep remission off adalimumab at 2 years. Median time between adalimumab discontinuation and the first clinical relapse was 14 months. No predictive factor associated with loss of deep remission in the year following treatment discontinuation was identified. No serious adverse event was reported.

Conclusion

In this first prospective trial exploring withdrawal of advanced therapy in early CD, 22.6% achieved deep remission at one year with adalimumab; among them, about a quarter maintained deep remission at two years. These results demonstrate that anti-TNF therapy should not be discontinued, even in patients with early CD.

Introduction

An important issue for unresectable advanced stage hepatocellular carcinoma (uHCC) patients with Child-Pugh class B liver cirrhosis (CP-B), is lack of safe treatment options that show therapeutic efficacy, thus it is considered to be an unmet need. Atezolizumab plus bevacizumab (At/Bv) and durvalumab plus tremelimumab (Dur/Tre) have each been used as first-line systemic immunotherapy for uHCC.

Aims & Methods

The present study aimed to elucidate clinical outcomes of uHCC patients with CP-B treated with those combination treatments. The records of 169 uHCC patients with CP-B in Japan, treated with At/Bv or Dur/Tre as first-line systemic therapy from 2020 to 2024 at participating institutions were examined (median age: 73 years, males: 143, Child-Pugh score 7:8:9 = 121:43:5, BCLC stage B:C = 65:104, At/Bv:Dur/Tre = 131:38). Each regimen was analyzed for therapeutic efficacy and safety, and the results compared, in a retrospective manner.

Results

Using RECIST, ver. 1.1, the objective response rate (ORR) was shown to be 25.9% in the At/Bv group, and 18.4% in the Dur/Tre group (p=0.08). Disease control rate (DCR) was significantly higher in the At/Bv group (64.9% vs. 39.5%, p=0.01). There were no significant differences between the groups for progression-free survival (PFS) [At/Bv vs. Dur/Tre=5.3 vs. 3.5 months (95% CI: 3.9–6.5 and 2.3–7.2, respectively), p=0.90], overall survival (OS) [10.5 vs. 12.5 months (95% CI: 9.1–13.3 and 7.9–NA, respectively), p=0.58], or post-progression survival (PPS) [4.9 vs. 7.5 months (95% CI: 3.7–7.5 and 2.2–NA, respectively), p=0.60]. The rate of incidence of immune-related adverse events (irAEs) of any grade was 11.5% in the At/Bv group and 23.7% in the Dur/Tre group (p=0.07), while irAEs of grade 3 or higher were noted in 3.1% and 15.8%, respectively (p=0.02) significantly greater in the Dur/Tre group).

Conclusion

The incidence rate of irAEs in each group was similar to that observed in clinical trials previously performed for these regimens. uHCC patients with CP-B, who received Dur/Tre had a greater rate of incidence of high-grade irAEs, while the At/Bv group had a better DCR, though there were no significant differences for PFS, OS, or PPS between the groups. Neither treatment was found to sufficiently improve the prognosis of uHCC patients with CP-B. Development of safe and effective treatment options for patients affected by uHCC, that can be administered even to those with CP-B remains necessary.

Disclosure

Atsushi Hiraoka: lecture fee Chugai, AstraZeneca, and Lilly.

Introduction

The optimal surgical approach to reduce recurrence rates after laparoscopic repair of paraesophageal hernia (PEH) is yet to be defined. The crural repair is challenged by both axial and transverse-lateral tension, which may compromise durability. The aim of this double-blind randomized clinical trial was to investigate whether a left-sided diaphragmatic relaxing incision in addition to standard crural repair and fundoplication reduces anatomical recurrence rates at one year postoperatively.

Aims & Methods

This study was conducted at two high-volume Swedish centers—Ersta Hospital (Stockholm) and Sahlgrenska University Hospital (Gothenburg)—between August 2019 and August 2023. Adult patients undergoing surgery for PEH were randomized 1:1 to either standard crural repair with total (360°) fundoplication (control) or the same procedure with the addition of a left-sided diaphragmatic relaxing incision covered by synthetic mesh (intervention). Patients with prior hiatal surgery, ASA class IV or above, type I hernia, major esophageal motility disorders, or any contraindication to fundoplication were excluded. Blinding for patients and assessors was maintained throughout follow-up. Pre- and postoperative assessments included computed tomography (CT), symptom questionnaires (Dakkak dysphagia score, Gastrointestinal Symptom Rating Scale [GSRS]), and quality of life (QoL, RAND-36). The primary outcome was radiologically confirmed PEH recurrence at 12 months.

Results

Of 103 patients screened, 76 were randomized (38 per group). Baseline characteristics were well balanced. CT was completed in 72 patients (95%) at 12 months. The recurrence rate was 66% in the control group and 54% in the intervention group (p=0.313). Three patients in the intervention group had asymptomatic CT verified herniation at the site of the diaphragmatic incision. There were no differences in recurrence size distribution (<4 cm vs >4 cm) between groups. Postoperative symptom assessment revealed significant improvements in dysphagia, reflux, indigestion, and abdominal pain in both groups, without intergroup differences. Physical QoL (PCS) improved significantlywhereas mental QoL (MCS) remained unchanged. Two deaths occurred within 90 days postoperatively (1 per group), yielding a 90-day mortality of 2.6%. Other complications included mediastinal abscess (n=1, intervention group) and need for postoperative endoscopic dilatation (n=5 in total). Operation time tended to be longer in the intervention group (150 vs 133 min; p=ns).

Conclusion

In this randomized, double-blind trial, the addition of a left-sided diaphragmatic relaxing incision to standard laparoscopic PEH repair did not improve anatomical recurrence rates, symptom relief or QoL at 12 months after surgery and should not be recommended for routine use. Alternative strategies to improve recurrence rates after PEH need to be explored in the future.

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