Introduction

The EXIT trial showed there is no difference between inflammatory bowel disease (IBD) patients who were in remission and withdrew anti-TNF therapy, and those who maintained anti-TNF therapy with respect to the percentage of sustained remission at 12 months. However, data of the long-term outcomes are crucial.

Aims & Methods

Aims: To compare long-term risk of relapse in IBD patients in remission who withdrew anti-TNF therapy versus those who maintained anti-TNF therapy, to analyse the response to anti-TNF resumption in those patients who relapsed after anti-TNF withdrawal, and to evaluate the overall success of the anti-TNF resumption strategy.
Methods: This study is an extension of the follow-up from the EXIT trial. Patients included in EXIT trial were IBD patients who have achieved clinical remission for ⩾6 months at standard anti-TNF dosage, with absence of significant endoscopic/radiological lesions, no previous IBD-related surgery, and ongoing immunomodulatory treatment. Patients were randomised either to maintain or to withdraw the anti-TNF therapy¹. The long-term outcomes of patients in sustained clinical remission who have completed the follow-up of EXIT trial per-protocol were analysed at the end of the EXIT trial. After that, patients were managed at the discretion of their physicians. Patients who were randomised in EXIT trial to continue with the anti-TNF comprised the maintenance arm (MA). For these patients, follow-up continued until either the anti-TNF resumption, or until the initiation of another biologic treatment or until the small molecule therapy (due to relapse or electively) or until the last visit (if no relapse occurred). Patients who were randomised in EXIT trial to withdraw the anti-TNF comprised the withdrawal arm (WA). For these patients, follow-up ended either at the time of relapse, at the withdrawal of anti-TNF treatment (electively, due to relapse, or adverse events), or at the last visit. The success of the anti-TNF resumption strategy was defined as the achievement and maintenance of clinical remission after restarting the anti-TNF therapy due to relapse, without experiencing adverse events or major complications (such as the need for surgery for IBD or the appearance of new perianal fistulas) that led to treatment withdrawal.

Results

125 patients were included, 63 in MA and 62 in WA. Median follow-up was 12 and 26 months in MA and in WA, respectively (p<0.05). The main characteristics of the study population are detailed in table 1. In MA, the cumulative incidence of relapse was 8% at 12 months, 47% at 24 months, and 65% at 36 months, whereas in the WA was 16% at 12 months, 39% at 24 months and 43% at 36 months of follow-up, (p=0.3). The incidence rate of relapse was 22% (95% CI 14-31) and 19% (95% CI 13-26) per patient-year of follow-up in MA and WA, respectively. In the multivariate analysis, having a fecal calprotectin at baseline of the EXIT trial >250 μg/g was the only variable associated with a higher risk of relapse (HR=3.94, 95% CI=1.92-8.06; p<0.0001). Of the 29 patients of WA who relapsed, 26 patients (90%) resumed the same anti-TNF and 69% of them achieved clinical remission. At the end the of follow-up, 16 out of 26 patients (62%) who restarted anti-TNF maintained remission, while 10 out of 26 patients (38%) discontinued anti-TNF: 4 due to non-response, 2 due to loss of response, and 4 due to adverse events. The proportion of adverse events was similar in the MA and the WA, 69% and 68%, respectively (p>0.05).

Conclusion

In the long-term analysis of the outcomes of patients included in EXIT trial, the withdrawal of anti-TNF therapy in patients with IBD in remission was not associated with higher risk of relapse. Resumption of anti-TNF after relapse recapture remission in the majority of patients. The anti-TNF withdrawal approach was safe.

Table 1. Characteristics of the study population at baseline.

References

1. Chaparro M., Donday MG., Barreiro-de Acosta M., Domènech E., Esteve M., García-Sánchez V., et al. Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial. Therap Adv Gastroenterol 2019;12. Doi: 10.1177/1756284819874202.

Disclosure

Manuel Barreiro-de Acosta has served as a speaker, consultant and advisory member for or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, GALAPAGOS, Pfizer, Sandoz, Biogen, Fresenius, Lilly, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte and Vifor Pharma.
María José Casanova, has received education funding from Pfizer, Takeda, Janssen, MSD, Dr. Falk, Shire, Ferring, Galápagos and Abbvie.
María Chaparro has served as speaker, consultant or research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Biogen, Gilead and Lilly.
Javier P. Gisbert has served as speaker, consultant, and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos, Lilly, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine and Vifor Pharma.
Ana Gutiérrez-Casbas has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Tillotts, Pharma, Chiesi and Otsuka Pharmaceutical.
Marisa Iborra reports grants and personal fees from MSD, Janssen, Abbvie, Takeda, Kern and Chiesi, during the conduct of the study.
Eduardo Leo has received grants or honoraria for scientific activities, presentations or as a scientific advisor for MSD, Pfizer, Abbvie, Takeda, Janssen, Tillotts Pharma, Shire Pharmaceuticals, Ferring, Dr. Falk Pharma, Adacyte and Otsuka Pharmaceutical
Montserrat Rivero has served as a speaker or advisory member from TaKeda, Janssen, Galapagos, Ferring and Pfizer.
Iago Rodríguez-Lago has received financial support for traveling and educational activities from or has served as an advisory board member for Abbvie, Adacyte, Celltrion, Chiesi, Danone, Ferring, Faes Farma, Janssen, Galapagos, MSD, Pfizer, Roche, Takeda, and Tillotts Pharma. IRL-L is supported by a research grant from Gobierno Vasco-Eusko Jaurlaritza [Grant No 2020111061] and by a research grant from Biobizkaia Bizkaia HRI [Grant No BCB/I/LIB/22/008].
Cristina Rubín de Célix has received education funding from Ferring, Tillotts Pharma, AbbVie, Norgine, MSD, Pfizer, Takeda and Janssen.
Manuel Van Domselaar has received educational funding from Janssen. Kern Pharma. and Takeda.
Rest of authors have nothing to declare.

Introduction

IBD is a global health problem. It is necessary to understand the evolution and treatment exposure in a cohort of newly diagnosed IBD patients in the biologic era in the South of Europe

Aims & Methods

Aims: 1) To describe the main epidemiological and clinical characteristics of patients at IBD diagnosis and the long-term outcomes; 2) to analyse the use of drugs for IBD, and the need of hospitalisations and surgeries; 3) to compare IBD management based on the type of disease and the resources of the hospitals.
Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD —Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified— during 2017 in the 17 Spanish regions were included. Patients who consented were followed-up for 5 years (yr) after diagnosis. Treatment was grouped into 5 categories: mesalamine (oral or topical), steroids (intravenous, oral, or topical), immunomodulators (thiopurines, methotrexate or cyclosporine), biologics (anti-TNF, vedolizumab, ustekinumab) or JAK inhibitors (JAKi), and surgery. Hospitals were classified into high resources and low resources ones. Cumulative incidence of exposure to each of the studied treatments was estimated by Kaplan-Meier curves; curves were compared with log-rank test.

Results

A total of 3,301 incident cases of IBD diagnosed during 2017 in 108 hospitals, covering over 22 million inhabitants in Spain (about 50% of the population), were enrolled into the follow-up study. Main characteristics of the cohort are summarised in table 1A and 1B. Median diagnosis delayed was 3.5 months (5.6 in CD and 2.7 in UC, p<0.001). During the 5-yr follow-up, 25% of UC patients progressed to more extensive involvement, while 8% of CD patients with inflammatory behaviour progressed to either stricturing or fistulising behaviour. Most of the patients who received mesalamine, corticosteroids, or immunomodulators initiated treatment within the first 2 years after diagnosis (figure 1). However, the cumulative incidence of biologics/JAKi usage steadily increased over time, reaching 49% by the 5-yr timepoint in CD. In terms of surgeries, a progressive increase in cumulative incidence was observed in CD; however, the incidence of colectomy remained stable in UC from the 2^nd year post-diagnosis. The management and progression of IBD unclassified were similar to that of UC. Regarding the type of hospital, a higher cumulative incidence of biologics/JAKi usage, hospitalisations, and surgeries was observed in CD at high resources hospitals. No differences were observed in the use of other therapeutic resources or the management of UC.

Conclusion

In the EpidemIBD large-scale epidemiological study, we have observed that the delay in diagnosing IBD is shorter than previously described. Approximately 50% of patients with CD and 20% of patients with UC end up receiving biologics/JAKi in the first 5 yrs following diagnosis. The percentage of patients undergoing surgery was lower than previously reported; in the case of UC, the majority of colectomies occurred within the first 2 yrs after diagnosis.

Disclosure

MDMA has received consulting and/or speaker fees from AbbVie, Pfizer, Takeda, Janssen, Tillotts Pharma and Galapagos; and has received research funding from Abbvie, Janssen and Pfizer.
RF-I has served as a speaker, advisory member or has received research funding from Takeda, MSD, Abbvie, Janssen, Pfizer, Palex, Shire Pharmaceuticals, TillottsPharma, Faes, Adacyte, Ferring and Casenrecordati.
R. Lorente has served as a speaker, or has received research or education funding from Abbvie, Pfizer, Takeda, Janssen and Galapagos.
IV has served as a Speaker, consultant and advisory member for and has received funding for: MSD, Abbvie, Pfizer, Ferring, Shire Pharmaceuticals, Takeda, Tillots, Jannsen y Galápagos.
EF-S Tillotts Pharma (speaker and travel grants), Ferring (speaker and travel grants) ), Faes (travel grants), MSD (speaker and travel grants), Abbvie (speaker and travel grants), Falk (travel grants), Shire (speaker and travel grants), Takeda (speaker and travel grants).
LAG has served as speaker or has received research or education funding from MSD; Abbvie; Kern Pharma; Ferring; Faes Farma; Shire Pharmaceuticals; Pfizer; Takeda; Janssen; Tillots Pharma and OtsuKa Pharmaceutical

Introduction

The true effect of having inflammatory bowel disease (IBD) in the development of infections has not been studied in depth since cohort studies are scarce and the results of studies are sometimes contradictory. Especially, this complication has not been addressed prospectively in an incident cohort of patients with IBD.

Aims & Methods

Aims: To assess, regarding infections in IBD: 1) incidence and type, 2) risk factors, 3) effect of type and the duration of IBD treatment, 4) impact in mortality 5) effect of IBD activity.
Methods: The INFEII registry (ClinicalTrials.gov: NCT02904590) is a prospective study promoted by GETECCU to determine the incidence and risk factors of infection in an inception cohort of patients with IBD and follow-up of at least 5 years. This longitudinal prospective study within the ENEIDA registry included incident cases with IBD. Patients were recruited between 2016 and 2020 with a planned follow-up of 5 years. All infections were detailed analysed. An infection was considered relevant when: 1) required hospital admission, 2) led to death or endangered the patient’s life, 3) was treated with specific antibiotics,4) occurred recurrently, and/or 5) required change/withdrawal of immunosuppressive treatment.

Results

The INFEII registry recruited 1456 patients from 28 centres throughout Spain. The median follow-up was 71 months (IQR 60-79 months). The description of the cohort is presented in Table 1. Of the 1456 patients, 580 (40%) presented at least one relevant infection. In total, 1321 infections were collected. One-hundred and seven infections (8%) required hospitalisation and four patients died (0.3%) over infection. Ninety-nine patients were lost to follow-up (22 died and 34 changed hospitals). The most prevalent infections were: ear-nose-throat in 238 cases, urinary tract infections in 237, respiratory in 234, COVID-19 in 133, skin infections in 127, dental in 64 and colitis/enteritis in 64. From the whole cohort and at some point, in time, 756 (52%) patients received 5ASA, 481 (33%) steroids (369 (25%) oral, 112 (7.7%) intravenous), 568 (39%) azathioprine, 72 (4.9%) methotrexate, 21 (1.4%) tofacitinib, 533 (37%) antiTNF, 141 (9.9%) ustekinumab and 77 (5.3%) vedolizumab. The effect of treatment and IBD activity in each infection is being analysed.

Table 1. Clinical characteristics of patients included in the INFEII study

Conclusion

Infections are frequent complications in patients with IBD, presented in 40% of them. Being a woman, having a history of past serious infections or occupational risk may be associated with infection occurrence. It has to be determined if IBD activity and treatment pose a greater risk for infections. This paradigmatic study implies the first use of the ENEIDA registry in prospective research.

Introduction

Anti-TNF are the first biologic treatment option in inflammatory bowel diseases (IBD). Few data is available on the long term risk of relapse after anti-TNF withdrawal in paediatric-onset IBD, especially at the population level.

Aims & Methods

All paediatric-onset (<17 years) IBD diagnosed between 1988 and 2011 were included in a prospective population-based study and were retrospectively followed until 2013. Among patients treated with first-line anti-TNF, the cumulative probability of relapse after anti-TNF withdrawal was evaluated using a composite outcome (intestinal resection, and/or flare-related hospitalization, and/or IBD treatment initiation, and/or active disease). Factors associated with relapse were investigated with a Cox model.

Results

Among a total of 1,344 patients (Crohn’s disease (CD): n=1,007; Ulcerative colitis (UC): n=337), 562 were treated with anti-TNF. Anti-TNF was stopped in 73 patients (CD: n=66; UC: n=7) during remission defined by Harvey-Bradshaw score < 4 in CD and Mayo score ≤ 2 in UC. Among them, median time to anti-TNF initiation was 1.6 years (IQR, 0.7-4.0) and median duration of treatment was 1.0 year (0.3-1.7). The first line anti-TNF therapy was infliximab in 68 (93%) patients. At anti-TNF withdrawal, 47 (64%) patients received immunosuppressant. The cumulative probability of relapse after anti-TNF withdrawal at 1, 3 and 5 years was respectively 62%, 85% and 93%. Median delay of relapse was 9.5 months (7.5-12.0). The cumulative probability of flare-related hospitalization at 1, 3 and 5 years was respectively 7%, 7% and 8%. No patient required intestinal resection after a median follow-up of 8.7 (5.8-13.8) years. In multivariate analysis, median time to anti-TNF initiation >1 year was the only factor associated with the risk of relapse (HR 0.58, CI95% [0.35-0.97], p=0.036). Among relapsers, 46 (63%) were retreated with anti-TNF. Retreatment with anti-TNF was effective in 45 (98%) patients after a median delay of 3.9 months (3.5-10.0). Infusion reaction occurred in only 2 patients.

Conclusion

In a population-based cohort of paediatric-onset IBD, the risk of relapse after anti-TNF withdrawal was high, but was not associated with major complication. Retreatment with anti-TNF was effective and well tolerated.

Disclosure

Consultant fees from Sandoz and AbbVie

Introduction

Inflammatory bowel disease (IBD) describes two chronic inflammatory intestinal diseases: Ulcerative Colitis (UC) and Crohn’s Disease (CD). Treatment of these conditions is often through immunosuppression to induce remission then maintenance. Cytomegalovirus (CMV) is a virus commonly found latent in all humans with seroprevalence rates existing between 40-100% depending on geographical location (1). Pathological reactivation of CMV is triggered by inflammation and immunosuppression; both present in the pathogenesis and treatment of IBD respectively (2). Consequentially, CMV reactivation occurs in IBD flare-ups around a rate of 25% (2) and greater than 30% in steroid-refractory patients (1, 3). Whether CMV reactivation is associated with escalating medical therapy, further hospital admissions, and worse clinical outcomes such as toxic megacolon or colectomy when compared to non-CMV associated flare-ups remains controversial. As such, the aims of this study were to follow up patients with IBD following an index episode of CMV colitis and analyse disease progression, relapse of CMV colitis, and clinical outcomes.

Aims & Methods

As such, the aims of this study were to follow up patients with IBD following an index episode of CMV colitis and analyse disease progression, relapse of CMV colitis, and clinical outcomes.
A retrospective study of patients treated at Royal Melbourne Hospital, Parkville, Australia treated between 2018-2023 was completed. Patients were included if they had a diagnosis of IBD, had positive immunohistochemistry for CMV on biopsy, and were treated with Ganciclovir or Valganciclovir for CMV colitis. Data collected included
demographic details and laboratory investigations at time of first episode of CMV colitis. Data regarding treatment for IBD and CMV colitis at time of CMV colitis was also collected. Outcome results were collected at 6-month and 12-month time points after first episode of CMV colitis. Fourteen patients were included in this study; 13 with UC and 1 with CD.

Results

Recurrence of CMV colitis occurred in 21% of cases at 6 months and 29% at 12 months. Additional courses of corticosteroids remained constant at 21% of cases at 6 and 12 months. Forty-three percent of patients had changed their biologic at 6 months and this stayed constant at 12 months. Similarly, 29% of patients had escalated their biologic dose at 6 months which was the same at 12 months. At 6 months, 43% of patients had been re-hospitalised due to IBD or CMV including 2 colectomies. At 12 months, these figures increased to 36% and 3 respectively. Disease remission was only achieved by 7% of patients at 6 months, increasing to 29% at 12 months.

Conclusion

While a descriptive study, our results when compared with previous studies (4) suggest that CMV colitis is a negative prognostic marker in patients with IBD, resulting in higher rates of hospitalisation, failed medical therapy requiring medication change or dose escalation, and colectomy. These risks may be greater at <6 months from index episode of CMV colitis. Further research regarding effective management of CMV colitis is needed to minimise poor outcomes in these patients.

References

1. Maher MM, Nassar MI. Acute cytomegalovirus infection is a risk factor in refractory and complicated inflammatory bowel disease. Digestive diseases and sciences. 2009;54:2456-62.
2. Kandiel A, Lashner B. Cytomegalovirus colitis complicating inflammatory bowel disease. Official journal of the American College of Gastroenterology| ACG. 2006;101(12):2857-65.
3. Cottone M, Pietrosi G, Martorana G, Casa A, Pecoraro G, Oliva L, et al. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn’s colitis. The American journal of gastroenterology. 2001;96(3):773-5.
4. Zhang M, Bai X, Zhang H, You Y, Lv H, Li Y, et al. The role of cytomegalovirus colitis on short- and long-term outcomes for patients with ulcerative colitis. Scandinavian Journal of Gastroenterology. 2022;57(3):282-9.