Introduction

Cyclical monoclonal antibody (mAB) therapy, defined as intermittent pausing of biological agents to reduce drug cost and risk of adverse events, has been proposed as a treatment strategy. There are few prospective discontinuation studies; most are uncontrolled, have small sample sizes, are retrospective, are short term, and do not directly compare multiple mABs. It is therefore unknown if treatment persistence is impaired following a drug holiday versus their initial trajectory. Whether persistence loss differs between mABs, is mitigated by immunomodulators or shorter drug holidays, is also unknown.

Aims & Methods

We aimed to evaluate the persistence of Crohn’s disease (CD) mABs with- and without drug holiday using a real world data registry. We interrogated the prospective population-based Persistence Australian National IBD Cohort (PANIC)5 registry of CD subjects up until Dec 2021. The PANIC registry includes the entire Australian population on advanced therapies. Drug holiday was defined as mAB discontinuation with recommencement of the same mAB after a >6-month dispensing gap. Non-persistence was defined as subsequent cessation of treatment for >6-months. Kaplan Meier survival curves were generated for persistence and compared using the log-rank test. Propensity score matched Cox proportional hazards regression models calculated hazard ratios (HR) and 95% confidence intervals (CI). P<0.05 was deemed statistically significant (SPSS, IBM, USA).

Results

In total 19,078 consecutive CD subjects (44.5% male, median age 39.0 years, 79,677 patient-years of prospective follow-up) were identified with 3,383 episodes of drug holiday (mean duration of 414 days) versus 28,584 episodes of continuous treatment as controls. Patients who resumed mAB therapy following a drug holiday had a statistically significant lower median persistence of 23 months versus 41 months for controls (-18 months; HR: 0.63, 95% CI: 0.60-0.66, P<0.001). TNF inhibitors (TNFi) and ustekinumab (UST) demonstrated significant loss of persistence following a drug holiday (both P<0.001) but not vedolizumab (P=0.63; Figure 1). Shorter versus longer median drug holiday duration did not impact persistence (P>0.05). Use of immunomodulator abrogated the loss of persistence of UST (P=0.15) but not TNFi (P<0.001). Propensity score matched independent predictors of non-persistence were drug holiday (HR: 0.72 [95%CI: 0:67-0.76]), TNFi, monotherapy, females, and bio-exposed status.

Conclusion

This study that recruited all CD subjects on advanced therapy in Australia showed pausing mAB therapy to be associated with a 37% decline in medication persistence for TNFi and UST, but not VED. Immunomodulator combination therapy mitigated the loss of persistence with UST but not TNFi. mAB drug holiday should be discouraged and closely monitored for disease relapse. These data do not support the cyclical use of mABs.

Disclosure

RL: advisory board: AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, Takeda; research grants: Joanna Tiddy USYD, McCusker Charitable Foundation, Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, MRFF

Introduction

Filgotinib, a selective JAK1 inhibitor, has emerged as a promising therapy for moderate-to-severe ulcerative colitis (UC). However, real-world data, especially in multi-refractory patients, remain scarce. The Filguito registry, conducted across 11 Andalusian centers, provides a comprehensive assessment of filgotinib’s effectiveness and safety over 12 months in routine clinical practice.

Aims & Methods

This ambispective, multicenter study included 77 UC patients treated with filgotinib. Clinical and biochemical parameters were collected at baseline, weeks 8 and 16, and months 6 and 12. Clinical remission (CR) was defined as a partial Mayo score <3; combined clinical-biochemical remission (CBR) as partial Mayo <3 plus fecal calprotectin <250 μg/g; and steroid-free remission (SFR) as partial Mayo <3 without corticosteroids since week 8. Effectiveness outcomes were stratified by prior exposure to advanced therapies.

Results

The study population had a mean age of 39.5 years and a mean disease duration of 13.5 years. Most patients (62%) presented with extensive colitis, and the majority had a history of multiple failed advanced therapies (mean 2.1). At baseline, disease activity was high, with a mean partial Mayo score of 5.6 and mean fecal calprotectin of 2,325.5 μg/g. Only a minority were corticosteroid-dependent at initiation.
Filgotinib induced rapid and sustained reductions in disease activity, with the partial Mayo score decreasing from 5.6 at baseline to 1.2 at 12 months (p<0.001). Fecal calprotectin levels fell by 76% (2,325.5 to 548.2 μg/g, p=0.006), and CRP declined significantly by year-end (12.4 to 3.1 mg/L, p=0.022). Clinical remission rates rose sharply to 56.9% by week 8, stabilizing at 53% by 12 months. Composite and steroid-free remission peaked at 32.8% and 45.8%, respectively, during follow-up (Table 1).
Differential Response by Prior Treatment Exposure
Patients with ≥2 prior advanced therapy failures showed markedly lower effectiveness:

• 12-month clinical remission: 32% vs. 58% in those with 1 prior failure (p=0.029).
• Steroid-free remission: 28% vs. 64% (p=0.014).
• Composite remission: <25% across subgroups, with no significant intergroup differences.

By the end of follow-up, 29.8% of patients had discontinued filgotinib, mainly due to lack of primary or secondary response. Only two patients stopped treatment because of adverse events (fever), and one due to pregnancy. No serious adverse events were reported, confirming a favorable safety profile in this real-world cohort.

Table 1: Effectiveness Outcomes

Timepoint	Baseline (n=77)	8 Weeks (n=70)	16 Weeks (n=49)	6 Months (n=46)	12 Months (n=29)	p¹
Partial Mayo Index (mean)	5.6	2.6 (<0.001)²	1.9 (<0.001)²	1.8 (<0.001)²	1.2 (<0.001)²	<0.001
CRP (mg/L, mean)	12.4	6.9 (0.567)²	7.2 (0.567)²	4.8 (0.079)²	3.1 (0.022)²	0.019
Calprotectin (μg/g, mean)	2325.5	1941.0 (0.628)²	1083.2 (0.036)²	813.7 (0.218)²	548.2 (0.005)²	0.006
Clinical Remission (%)	6.5%	56.9% (<0.001)³	54.1% (<0.001)³	54.1% (<0.001)³	53.1% (<0.001)³	-
Clinical-Biochemical Remission (%)	1.3%	25.0% (<0.001)³	16.4% (0.004)³	32.8% (<0.001)³	22.4% (0.009)³	-
Steroid-Free Remission (%)	-	45.8%	37.7% (0.333)³	42.6% (0.014)³	38.8% (0.002)³	-
Treatment Discontinuation	-	11/77 (14.2%)	14/77 (18.1%)	20/77 (25.9%)	23/77 (29.8%)	-

¹ Friedman test for related samples (two-way ANOVA by ranks).
² Pairwise comparisons using the Friedman test.
³ McNemar test for related samples.

Conclusion

In this real-world, multicenter Andalusian cohort of patients with refractory UC, filgotinib demonstrated sustained clinical and biochemical effectiveness over one year, with a favorable safety profile. Although response rates were lower in patients with multiple prior advanced therapy failures, clinically meaningful improvements were observed even in this challenging population. These results support filgotinib as an effective and safe therapeutic option for UC in routine clinical practice

Introduction

Chronic intestinal pseudo-obstruction (CIPO) is a rare, heterogeneous, and challenging gastrointestinal motility disorder lacking clinical guidelines in adults.

Aims & Methods

We aimed to develop an international consensus among international experts in gut motility on the diagnosis and management of CIPO based on existing literature and expert opinion. Two experts from each continental motility society and experts on pathology, surgery, and nutritional aspects of CIPO were selected for participation. A list of >130 statements was drafted, subdivided into 11 topics. After revisions and validation by the experts of the list of statements, a systematic literature review was performed to summarize available data on every statement. Using a Delphi process of 3 voting rounds, consensus statements were identified (defined as >80% agreement).

Results

Consensus was reached for 77/139 statements. The panel defined CIPO as symptoms caused by severe small bowel dysmotility without mechanical obstruction, and with documented dilated intestine or air/fluid levels, mimicking mechanical obstruction. Pseudo-obstructive episodes or continuous pseudo-obstructive symptoms were considered a cardinal feature of CIPO. Abdominal pain, bloating, and distension were also considered cardinal symptoms, while nausea/vomiting, diarrhea, or constipation were considered associated symptoms.
Radiographic imaging was considered mandatory in the diagnostic work-up, to confirm intestinal dilation or air/fluid levels and to rule out mechanical obstruction.. No other diagnostic test was considered indispensable for the diagnosis, including endoscopy, manometry, or laparoscopy. Screening for secondary causes of CIPO, including systemic sclerosis, paraneoplastic disease, or infectious disease, was supported, with a possible role for transmural histology. Differential diagnoses, including drug adverse effects, adhesions, or enteric radiation, should be ruled out. The experts also recommended screening for complications such as nutritional deficiencies and osteoporosis.
Management requires dietary adjustment, with supplementation for deficiencies, and setting up home parenteral nutrition if enteral nutrition fails. Small intestinal bacterial overgrowth was recognized as a main contributor to symptom aggravation and should be treated by intermittent antibiotics without the need for breath testing confirmation in patients with CIPO. There was no consensus regarding choice or efficacy of drug therapy, including prokinetics (e.g. pyridostigmine, prucalopride), laxatives, or somatostatin analogs. Opioids and surgical resections should be avoided; although endoscopic or surgical decompression procedures may be helpful in acute or persisting pseudo-obstructive symptoms.

Conclusion

This expert consensus developed key statements for the definition, diagnosis, and treatment of CIPO in adult patients. It provides the opportunity to harmonize the management of these patients and to highlight the gaps in the current literature.

Disclosure

Jan Tack has given Scientific advice to Aclipse, Adare, AlfaSigma, Clasado, Danone, Falk, FitForMe, Ironwood, Kyowa Kirin, Menarini, Promed, Ricordati, Takeda, Truvion, Tsumura, Zealand Pharmaceuticals, has received research support from Biohit, Kiowa Kirin, ProMed, Sofar and Takeda, and has served on the Speaker bureau for Abbott, Bio-Codex, Mayoly, Menarini, ProMed, Reckitt-Benckiser, Schwabe, Takeda, Thai Meiji and Truvion Pharmaceuticals.