Introduction

Short bowel syndrome (SBS) is the most common cause of intestinal failure (IF) in children and is generally managed using parenteral nutrition and/or intravenous fluids (PN/IV). Long-term PN/IV can cause potentially life-threatening complications. Patients may receive teduglutide (TED) to encourage adaptation of the remaining intestine and to reduce dependence on PN/IV. Short-term studies have shown that TED is effective and has an acceptable safety profile in children and adults with SBS-associated IF (SBS-IF). However, assessment of long-term treatment with TED in paediatric patients with SBS-IF is limited.

Aims & Methods

We report real-world long-term safety and effectiveness data of TED from a paediatric cohort enrolled in the prospective, multinational SBS Registry (NCT01990040; EUPAS7973). Data were analysed cumulatively for up to 6 years between enrolment and interim data cut-off (June 23, 2014 to June 30, 2023). Patients were categorised based on whether they received TED (ever-treated; received ≥1 dose of TED 0.05 mg/kg/day [median]) or never received TED (never-treated; received PN/IV for ≥6 months before study entry). Safety endpoints included: occurrence of colorectal cancer in patients with any remnant colon; other malignancy; colorectal polyps; and adverse events (AEs). Effectiveness endpoints included clinical response (≥20% reduction in PN/IV volume from baseline) and change from baseline in volume of PN/IV (per weight [L/kg]) and number of days/week receiving PN/IV.

Results

In total, 398 paediatric patients were enrolled: 266 never-treated, 132 ever-treated (per-protocol set, n=397; 266 never-treated, 131 ever-treated). Patients had a mean (standard deviation [SD]) age of 5.4 (4.01) years (ever-treated 6.8 [4.12] years; never-treated 4.8 [3.80] years) and the majority were male (63.7%; ever-treated 68.7%; never-treated 61.3%). The median (range) length of exposure in ever-treated patients was 29.0 (1.15–106.61) months.
No new cases of colorectal cancer or new/worsening colorectal polyps were reported between baseline and interim cut-off. New/worsening malignancies were reported for one never-treated patient. A greater proportion of ever-treated patients reported AEs (87.0% vs 74.4%) and serious AEs (SAEs; 72.5% vs 59.0%) than never-treated patients. AEs and SAEs related to TED were reported in 15.3% and 6.1% of ever-treated patients, respectively. There were no allergic or hypersensitivity reactions to TED. The most common TED-related AEs were vomiting (3.8%) and abdominal pain (2.3%). Fatal events were recorded for one ever-treated and three never-treated patients.
A greater proportion of ever-treated patients had achieved a clinical response (year 1, 18/30, 60.0%; year 3, 11/17, 64.7%) than never-treated patients (year 1, 23/100, 23.0%; year 3, 17/82, 20.7%). Ever-treated patients had a greater mean (SD) reduction from baseline in PN/IV volume (L/kg; ever-treated: year 1, −39.4% [35.97], n=19; year 3, −61.6% [23.64]; n=7; never-treated: year 1, −21.1% [50.70], n=80; year 3, −34.4% [36.83], n=49) and number of days/week receiving PN/IV (ever-treated: year 1, −1.6 [2.16], n=30; year 3, −1.5 [1.77], n=17; never-treated: year 1, −1.0 [2.22], n=100; year 3, −0.6 [1.51]; n=82) than never-treated patients.

Conclusion

This 6-year interim analysis of real-world data from a large cohort of paediatric patients with SBS-IF supports that the safety profile of TED is consistent with the previous 5-year follow-up and suggests that TED improves intestinal adaptation in paediatric patients with SBS-IF over a 3-year period.

Disclosure

Palle B Jeppesen: compensation received from Takeda as a member of the Scientific Advisory Committee for the SBS Registry study; commercial relationships as consultant and speaker with Albumedix, ArTara Therapeutics, Baxter, Coloplast, Ferring Pharmaceuticals, Fresenius Kabi, GLyPharma Therapeutic, Ironwood Pharmaceuticals, Naia Pharmaceuticals, NorthSea Therapeutics, Novo Nordisk Foundation, Protara Therapeutics, Takeda, Therachon, VectivBio and Zealand Pharma.
Martina Kohl-Sobania: compensation received from Takeda as a member of the Scientific Advisory Committee for the SBS Registry study; study investigator for NPS Pharmaceuticals and Takeda; honoraria from Aposan, Takeda and Tauro-Implant as a speaker; advisory board member for Takeda.
Francisca Joly: compensation received from Takeda as a member of the Scientific Advisory Committee for the SBS Registry study; study investigator for NPS Pharmaceuticals, Takeda, VectivBio and Zealand Pharma; advisory board member for Alira Health, ArTara Therapeutics, Baxter, M3E Solutions, Takeda, Therachon, VectivBio and Zealand Pharma; commercial relationships as consultant and speaker for Baxter, B. Braun, Fresenius Kabi, Nestlé Health Sciences, Takeda, Therachon and Théradial.
Joel B Mason: compensation received from Takeda as a member of the Scientific Advisory Committee for the SBS Registry study; research support from Takeda as a site for the study; compensation from Care/of, a producer of nutritional supplements; honoraria from UpToDate, a web-based medical information platform, for authoring chapters.
Johane P Allard: compensation received from Takeda as a member of the Scientific Advisory Committee for the SBS Registry study; fees from Takeda as a consultant and speaker, and research support from Takeda as a study site principal investigator (PI); research support from Fresenius Kabi and OMS as a PI; honoraria from Baxter as a speaker and consultant; research support from Zealand Pharma as a site PI.
Ulrich-Frank Pape: compensation received from Takeda as a member of the Scientific Advisory Committee for the SBS Registry study; honoraria from Takeda as a consultant and speaker, and research support from Takeda, VectivBio and Zealand Pharma as a study site PI.
Loris Pironi: compensation received from Takeda as a member of the Scientific Advisory Committee for the SBS Registry study; advisory board member for Baxter, NorthSea Therapeutics and Takeda.
Gabriel E Gondolesi: speaker for Takeda; compensation received from Takeda as a member of the Scientific Advisory Committee for the SBS Registry study; received investigator-initiated research grant from Takeda.
Lauren K Schwartz: compensation received from Takeda as a member of the Scientific Advisory Committee for the SBS Registry study; speaker for Bristol Myers Squibb; advisory board member for Takeda.
Pinggao Zhang, Sasan Sabrdaran and Yi Wen Huang: employees of Takeda Pharmaceuticals U.S.A., Inc. and receive stock and/or stock options.
André Gabriel: former employee of Takeda Pharmaceuticals U.S.A., Inc. who received stock and/or stock options.

Acknowledgements: This study was funded by Takeda Pharmaceuticals U.S.A., Inc., MA, USA. Medical writing support, funded by Takeda Pharmaceuticals U.S.A., Inc., was provided by Elizabeth Coe, PhD of PharmaGenesis Cardiff, Cardiff, UK.

Introduction

Upadacitinib, a selective JAK inhibitor, is approved for moderate-to-severe Crohn’s disease (CD). However, real-world data on its effectiveness and safety, particularly in highly refractory populations, remain scarce. The UPITA-Crohn registry was established to evaluate the outcomes of upadacitinib in clinical practice across multiple centers in Andalusia, Spain.

Aims & Methods

This ambispective, multicenter registry included 142 patients with refractory CD treated with upadacitinib in 12 Andalusian hospitals. Clinical and biochemical data were collected at baseline, weeks 12 and 16, and at 6 months. Clinical remission (CR) was defined as a Harvey-Bradshaw Index (HBI) <5; clinical-biochemical remission (CBR) as HBI <5, CRP <5 mg/L, and fecal calprotectin <250 μg/g; and steroid-free remission (SFR) as HBI <5 without corticosteroids from week 12. Outcomes were also analyzed overall and according to prior exposure to advanced therapies.

Results

The UPITA-Crohn registry cohort included 142 patients with refractory Crohn’s disease. The mean age was 40.8 years (range 18–76), with 40% male. The mean disease duration at the time of upadacitinib initiation was 13.3 years (range 1–42), with a mean of 2.7 failed advanced therapies, highlighting a population with longstanding and complex disease. Most patients had ileocolonic involvement (50%), 22% had perianal disease, and 32% had previously undergone resective surgery.
The majority (74.4%) received induction with upadacitinib 45 mg for 12 weeks. At week 12, clinical remission was achieved by 54% of patients, with 15% reaching clinical-biochemical remission. At 6 months, among those still on treatment, 48.3% maintained clinical remission, 16.1% achieved clinical-biochemical remission, and 18.4% achieved steroid-free remission (Table 1).
When stratified by prior therapy, 6-month clinical remission was similar between patients with ≥2 prior advanced therapies (48.5%) and those with only 1 prior therapy (47.4%), with no significant difference. Steroid-free and clinical-biochemical remission rates were also slightly higher among less refractory patients, but differences were modest.
A total of 31 patients (21.8%) discontinued upadacitinib before 6 months, mainly due to primary non-response (70.9%). Adverse events were reported in 21.1% of patients, most commonly infections (9 cases), acne (7), transient transaminase elevation (5), and herpes zoster (2). Seven discontinuations were due to serious adverse events, including thrombosis, stroke, myocardial infarction, fever, and severe infections.

Table 1: Effectiveness Outcomes

Conclusion

Upadacitinib demonstrated meaningful effectiveness and a manageable safety profile in a real-world cohort of refractory Crohn’s disease patients. Notably, clinical remission rates remained stable even in those with multiple prior advanced therapies, suggesting upadacitinib may be a valuable option for patients with limited alternatives.

Introduction

​​​​​Concerns regarding colorectal cancer in short bowel syndrome (SBS) patients receiving teduglutide (TED) treatment have led to the recommendation of colonoscopy for screening and surveillance.^1,2 While there are reports of new small bowel polyps in TED patients, data on small bowel cancer risk and surveillance are lacking.^3,4 This study aims to evaluate the feasibility and effectiveness of using double-balloon enteroscopy (DBE) for surveillance in SBS patients undergoing TED treatment.

Aims & Methods

Data from patients with SBS in TED treatment who underwent DBE within a year of starting TED at a tertiary referral center for enteroscopy between December 2019 and October 2023 were collected. The primary endpoints were technical success, adverse events, and total enteroscopy rates. Secondary endpoints included the incidence of small bowel polyps and residual small bowel length measurement.

Results

Nine patients (7 female, median age 65.5, IQR 58-79) with SBS (22% type 1, 55.6% type 2, 22.2% type 3-SBS) underwent DBE (10 anterograde, 2 retrograde) under procedural sedation. Crohn’s disease (33.3%) and post-surgical complications (33.3%) were the most frequent causes of SBS. The median interval from TED prescription to DBE surveillance was 9.1 months (IQR 3.2-32.9). The median depth of maximal insertion was 85 cm (IQR 50-187). No adverse events occurred during all the procedures. The total enteroscopy rate was 75% (80% [8/10] of anterograde DBEs, 50% [1/2] of retrograde DBEs). Panenteric DBE allowed the estimation of small bowel residual length in all cases (2/2) where this important clinical information was unknown and revealed a different residual small bowel length compared to surgery in 44% of patients. No small bowel malignancies were detected during the study period.

Conclusion

DBE surveillance for small bowel malignancy in SBS patients undergoing TED treatment is feasible and effective. Total enteroscopy can be frequently achieved with a single endoscopy in these patients, allowing easy oncologic surveillance.

References

1. Revestive (teduglutide). Summary of product characteristics. Takeda; August 2022. Accessed 23 March 2024. https://www. medicines.org.uk/emc/product/3382/smpc
2. Pironi L, Allard JP, Joly F, et al. Use of teduglutide in adults with short bowel syndrome-associated intestinal failure. Nutr Clin Pract 2024;39:141-153.
3. Pevny S, Pape UF, Elezkurtaj S, et al. De Novo Development of Distal Jejunal and Duodenal Adenomas After 41 Months of Teduglutide Treatment in a Patient With Short-Bowel Syndrome: A Case Report. JPEN J Parenter Enteral Nutr 2021;45:652-656.
4. Ukleja A, Alkhairi B, Bejarano P, et al. De Novo Development of Hamartomatous Duodenal Polyps in a Patient With Short Bowel Syndrome During Teduglutide Therapy: A Case Report. JPEN J Parenter Enteral Nutr 2018;42:658-660.