Introduction

Advanced combination treatment (ACT), defined as the use of two biologics or a biologic and a small molecule drug with distinct mechanisms of action, is increasingly adopted for refractory inflammatory bowel disease (IBD) and overlapping immune-mediated inflammatory diseases (IMIDs). Despite promising clinical results, the immunological consequences of ACT remain poorly characterized. Here, we investigated how two ACT regimens—anti-TNF + anti-integrin and anti-TNF + anti-IL-23—shape the peripheral CD3⁺ T cell landscape at single-cell resolution, with a focus on clonotype architecture, repertoire diversity, and antigen specificity.

Aims & Methods

We aim to characterize the peripheral CD3⁺ T cell transcriptional landscape and clonal architecture in patients with refractory IBD who achieved clinical response following initiation of two different ACT regimens: anti-TNF + anti-integrin α4β7 and anti-TNF + anti-IL-23. Peripheral blood mononuclear cells (PBMCs) were collected from six patients with Crohn’s disease who achieved clinical response to ACT. Four patients received anti-TNF + anti-integrin α4β7, and two received anti-TNF + anti-IL-23. CD3⁺ T cells were isolated and analyzed via single-cell RNA sequencing (scRNA-seq) coupled with paired T cell receptor (TCRα/β) sequencing. Cell state annotations were performed using supervised deconvolution against the scIBD reference atlas, and TCR repertoire metrics (diversity, clonality, evenness) were computed to assess clonal expansion dynamics.

Results

All patients included demonstrated clinical improvement, underscoring the immunological relevance of the findings. Single-cell transcriptomic and TCR repertoire profiling uncovered distinct treatment-specific patterns in peripheral T cell states and clonal architecture. In the anti-TNF + α4β7 group, there was marked enrichment of CD4⁺ tissue central memory T cells (CD4⁺ tissue-Tcm) and CD4⁺ naïve T cells (CD4⁺ Tn), along with greater TCR diversity, reduced clonal dominance, and enhanced repertoire evenness. In contrast, the anti-TNF + IL-23 group exhibited a marked enrichment of CD8⁺ naive T cells (CD8⁺ Tn) and a repertoire characterized by reduced diversity and pronounced oligoclonal expansion.

Conclusion

In difficult-to-treat IBD patients who achieved clinical response to ACT, distinct patterns of immunological remodeling emerged depending on the therapeutic combination. Treatment with anti-TNF + anti-integrin was associated with a diversified, polyclonal T cell repertoire consistent with a systemic rebalancing of the adaptive immune response, whereas anti-TNF + anti-IL-23 drove more focused, oligoclonal expansions indicative of selective immune activation. These divergent signatures underscore mechanistically distinct pathways of immune reprogramming and highlight the potential of T cell–based immuno-profiling to inform the rational selection of biologic combinations. Incorporating single-cell and TCR repertoire analyses into ACT trials may enable a precision medicine framework for optimizing treatment strategies in IBD.

References

Danese S, Solitano V, Jairath V, Peyrin-Biroulet L. The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment). Gut. 2022 Dec;71(12):2380-2387. doi: 10.1136/gutjnl-2022-327025. Epub 2022 Jun 14. PMID: 35701092.

Disclosure

Virginia Solitano has received speaker fees from Pfizer and consultancy fees from Johnson & Johnson. Vipul Jairath has received consultancy/advisory board fees from AbbVie, Alimentiv Inc., Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Topivert, Ventyx, and Vividion; and speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi. Silvio Danese has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenixa, UCB Inc, and Vifor; and lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer, and Takeda. The other authors have nothing to disclose.

Introduction

Primary aim: To assess the retention rate of ustekinumab treatment in patients with ulcerative colitis (UC).
Secondary aims: To assess the short-term effectiveness, the durability of response, and the tolerability of ustekinumab in clinical practice.

Aims & Methods

Retrospective, multicenter study including UC patients who had received the first ustekinumab dose at least 16 weeks before inclusion. Patients were followed-up from the first ustekinumab dose to treatment discontinuation or last visit, whichever came first. Only patients with active disease [Partial Mayo Score (PMS)>2] at ustekinumab start were considered in the effectiveness analysis. Clinical effectiveness was based on PMS. Patients who stopped ustekinumab before their last visit were considered non in remission at subsequent time points (negative imputation).

Results

376 patients have been included so far (91% had PMS >2 at ustekinumab start, 96% had been exposed to biologics, and 25% had failed to anti-TNF, vedolizumab and tofacitinib). At baseline, 50% of patients were under mesalamine, 24% under steroids, and 6% under thiopurines. 74% of patients started the maintenance treatment with 90 mg every-8-weeks, and 5% with 90 mg every-12-weeks subcutaneously; 8% of patients received ustekinumab intravenously as maintenance treatment from the beginning. 100 patients (27%) withdrew ustekinumab during follow-up [median=12 months (m)]. Incidence rate of ustekinumab discontinuation was 21% per patient-year of follow-up. The probability of maintaining ustekinumab was 98% at 1 m, 90% at 6 m, 78% at 12 m, 71% at 18 m, and 66% at 24 m. Main reasons for ustekinumab withdrawal were primary non-response (42%) and loss of response (30%). Anaemia at baseline (HR=1.7, 95%CI=1.1-2.6) was associated with higher risk, while concomitant treatment with mesalamine was associated with lower risk (HR=0.6, 95%CI=0.4-0.9), of ustekinumab discontinuation. The proportion of patients in clinical remission (CR) was 37% at week (w) 4, 49% at w 8, and 48% at w 16. To have moderate-severe vs. mild disease activity at baseline (OR=0.2, 95%CI=0.1-0.4) and to have failed to both anti-TNF and vedolizumab (OR=0.6, 95%CI=0.4-0.9) were associated with lower CR at week 16. A total of 83 (31%) patients among those with active disease at baseline and with at least response during the induction, lost response during a median follow-up of 12 months (IQR=6-18 months). The probability of maintaining response was 82% at 6 m, 72% at 12 m, and 61% at 24 m. The incidence rate of loss of response was 27% per patient-year of follow-up. In the multivariate analysis, to have achieved CR during the induction was the only variable associated with lower risk of loss of response (OR=0.5, 95%CI=0.3-0.9). The dose was escalated in 61% of patients with loss of response, and 82% improved (53% had CR); an intravenous reinduction was given in 19%, and 50% improved (31% had CR). The proportion of patients in CR during follow-up was 58% at 12 m, 48% at 24 m, and 41% at 36 m. A total of 69 patients (18%) had at least one adverse event, being infections the most frequent ones (8%). Ustekinumab was withdrew in 5 (1.3%) patients.

Conclusion

In the largest study performed so far on ustekinumab in UC in real life, ustekinumab has shown to be effective in inducing remission even in highly refractory UC patients. A relevant proportion of patients discontinue the treatment, mostly due to primary failure and loss of response. Dose escalation is effective to regain response after loss of efficacy. The safety profile is similar to that previously reported.

Disclosure

This is an investigator-initiated study with financial support from Janssen (CNTO1275UCO4008).

Introduction

MAESTRO-NASH (NCT03900429) is an ongoing 54-month, randomized, double-blind, placebo-controlled Phase 3 trial evaluating efficacy of resmetirom in patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH/MASH) and fibrosis. 966 patients with biopsy confirmed NASH were randomized 1:1:1 to resmetirom 80 mg, resmetirom 100 mg, or placebo once daily. Dual primary endpoints at Week 52 were achieved with both resmetirom 80 mg and 100 mg: NASH resolution with no worsening of fibrosis (NR) or ≥1-stage improvement in fibrosis with no worsening of NAS (FI). The benefit of resmetirom in patients with and without indicators of increased alcohol consumption above protocol-allowed limits for NASH/MASH was assessed on biopsy endpoints and MRI-PDFF (liver fat reduction).

Aims & Methods

Carbohydrate Deficient Transferrin (CDT) was collected longitudinally in all patients over 52 weeks. Post-randomization, a PEth test was performed in patients suspected of increased alcohol consumption. Patients with baseline or post-baseline CDT >2.5% (ULN 2.47) and/or a PEth >20ng/ml (ULN 20ng/ml) were assigned to a possible “MetALD” subgroup. Analyses were performed on 782 patients who had both a baseline and Week 52 biopsy.

Results

Of the 782 patients, 75 patients (9.6%) were included in the MetALD subgroup and 707 were not. Baseline characteristics, mean (SD), for the MetALD and non-alcohol subgroups included Age=57.7 (10.5), 60.1 (10.7); percent male=59%, 42%; Presence of diabetes=50.7%, 67.9%; CDT%=2.2 (1.0), 1.6 (0.3); BMI 33.0 (5.5), 35.8 (6.6); MRI-PDFF=21.7% (7.4), 17.4 (6.5), Fibroscan VCTE=13.4 (6.7), 13.2 (6.6); Fibroscan CAP=348.5 (38.5), 347.0 (38.7); FIB-4=1.67 (0.69), 1.37 (0.66); AST=45.6 (21.8), 40.3 (22.9); ALT=55.2 (24.8), 55.5 (32.2); GGT=117.9 (170.8), 75.3 (85.6); Bilirubin=0.69 (0.31), 0.65 (0.29); MCV=92.3 (5.8), 90.3 (5.6); Platelets=200, 229; NAS (median)=5 (5,6), 5 (5,6); and %F3=66.7, 62.5.
For the group of patients with low or no alcoholic consumption: Patients treated with 80 mg and 100 mg resmetirom doses (n=224 and 228, respectively): 29.9% and 36% had NR, 29% and 33.3% had FI, 59.2% and 71.2% showed a ≥30% reduction from baseline in MRI-PDFF. For patients treated with placebo (n=255), the corresponding results were 10.3%, 13.7%, and 24.5%.
For the possible MetALD group: Patients treated with 80 mg and 100 mg resmetirom doses (n=34 and 20, respectively): 29% and 35% had NR, 35% and 30% had FI, and 88% and 81% showed a ≥30% reduction from baseline in MRI-PDFF. For patients treated with placebo (n=21), the corresponding results were 10%, 19%, and 14%.

Conclusion

A total of 75 (9.6%) of patients had possible MetALD during the first 52 weeks of
MAESTRO-NASH. Baseline characteristics showed a higher mean GGT and FIB-4 in the MetALD versus
low alcohol group. Response rates to resmetirom in patients with suspected MetALD were similar to
those without MetALD.

Disclosure

Authors are investigators in the MAESTRO-NASH trial or employees of Madrigal Pharmaceuticals.

Introduction

Gastroenterologists generally undergo gastroenterology (GI) training during their childbearing years, making pregnancy while training a highly important topic regarding family-work balance. The aim of this study is to assess the challenges GI trainees encounter during pregnancy and parenthood.

Aims & Methods

A questionnaire was sent out via social media and email, targeting doctors who were pregnant or had a pregnant partner during their GI training in the last 10 years.

Results

Forty-six women (mean age 35.5 ±3.76, 93.4% from European countries). Of these, 56.5% had one pregnancy during training, 30.4% had two and 13.1% had three pregnancies. Fifteen males (mean age 35.2 ±3.76, 93.3% from European countries) also answered the questionnaire. Age at first pregnancy was similar between males (30.6 years) and females (30.5 years).
Most women (84.7%) reported worrying that they would be perceived negatively when they asked for changes in their work schedule due to the pregnancy. While 67.4% reported that their colleagues were accommodating, only 56.5% felt that it was easy to talk to their training coordinators about the pregnancy. Furthermore, 69.5% were concerned that the pregnancy would negatively impact their training.
Nearly all women participants (97.8%) were working more than 40 hours before the pregnancy. Of these, 78.2%, 63% and 32.6% continued to work more than 40 hours per week in the first, second and third trimesters, respectively. Worryingly, 56.5% had at least one complication during pregnancy or delivery. Participants reported several hazards that weren’t addressed during pregnancy, namely exposure to non-scavenged anaesthetic gases (47.8%), scope locator (36.9%), blood-borne illnesses (34.8%) and radiation (15.2%), and long endoscopy sessions (28.2%).
Of the participants who had returned to work after the birth of the child (n=44 females, n=15 males), men worked full-time more often than women (92.9% vs 59.5%, p=0.02).
Both genders had difficulty coping with parenthood, with only 19% of women and 33.3% of men stating that it was easy to adapt to being back at work and having a young child (p=0.25). They also reported feeling less productive at work than before (females: 54.8%, males: 40%, p=0.32).
Regarding the responsibility of caring for the child when they are unwell, 92.9% of the men reported that the child is taken care of by the other partner. In contrast, women reported it was themselves (36.4%) or other relatives (34.1%) who took care of the child; only 12.6% stated it was her partner who did it. Women reported feeling guilty towards colleagues for taking time off work to be with their child (35% females vs 6.7% males, p=0.03.)
Trainees felt that having children will impair their career progress (56.1% females, 40% males, p=0.29). However, females were more often convinced that having children made them appear less ambitious than their peers (60.4%), compared to males (26.7%), (p=0.02).

Conclusion

Pregnant trainees face numerous concerns during their pregnancy, both physical and psychological. Training centres need to carry out a formal risk assessment for all pregnant trainees to address possible hazards. Whilst parenthood strongly impacts on both male and female trainees, women tend to carry more burden regarding care for the child. There is the need to support and normalize pregnancy and parenthood during training, to achieve a healthy family-life-work balance.