Introduction

For decades, corticosteroids have been the first-line therapy in patients with severe ulcerative colitis (UC), however 30-40% of patients fail to respond and require second-line rescue therapy with cyclosporine (CsA) or infliximab to avoid colectomy.

Aims & Methods

We conducted a single-center, retrospective study including all patients with active severe, steroid-refractory UC and with at least one year follow-up, to assess the short- and long-term effectiveness and safety of CsA therapy. Disease severity was defined according to Mayo disease activity index. Patients with a pMayo score of ≥7 and an eMayo score of ≥2 were enrolled, and received 4 mg/kg/day CsA IV for 5-7 days for second-or third-line rescue therapy between 2001 and 2023. IV CsA therapy was followed by oral CsA in case of clinical response. Colectomy-free survival was assessed using Kaplan-Meier analysis. Multivariable logistic regression analyses were performed to identify the predictive value of various factors for therapeutic response to CsA and colectomy during or after CsA treatment.

Results

Ninety-two steroid-refractory UC patients (54.4% male, mean age: 40.0 ± 14.0 years, median disease duration: 4.0 years) were included with the median follow-up time of 14.0 years (IQR:7-18). Clinical response was achieved in 59/92 (64.1%) patients, and clinical remission was observed in 22/92 (23.9%) patients after the IV phase. During oral CsA therapy (10.4 ± 11.7 months) relapse rate was 42.0%, whereas 33 (40.7%) patients achieved or maintained remission until treatment discontinuation. Remission with oral CsA therapy was significantly higher among those who received concomitant immunomodulator treatment (p=0.004, OR:6.98, 95% CI:1.9-26.4). 20/92 (21.7%) patients underwent colectomy during CsA therapy, while a total of 45 (48.9%) patients required surgery at the end of follow-up. Non-response to IV CsA was the only predictor of colectomy during CsA therapy (p=0.04. OR: 0.17, 95% CI:0.03-0.94). No predictors for the effectiveness of the IV CsA could be found. Neither the need for colectomy during CsA therapy (p=0.33), nor the rate of remission with oral CsA (p=0.49) was influenced by the prior use of biologics. Remission with oral CsA was found to be the only predictor of colectomy within 3 years after CsA discontinuation. The probability of colectomy-free survival was 74.7%, 62.6%, 57.1% and 45.6% at 1, 3, 5 and 14 years. In 52 patients (64.1%), biological therapy was needed after an average of 7.2 (± 6.74) months from the start of CsA. Immunomodulators were used in 50 out of 89 patients following CsA discontinuation, as maintenance therapy or as part of combination therapy. Adverse events (AEs) occurred in 53.3% of patients, 57.2% of them required a dose reduction or treatment discontinuation. AEs were mainly reversible, but 1 patient died of opportunistic infections (acute tuberculous pneumonia). The occurrence of AEs was not associated with the use of concomitant immunomodulators (p=0.92). Malignancy was observed in 5 patients during follow-up, mainly melanoma and non-melanoma skin cancer.

Conclusion

CsA is an effective therapeutic option for avoiding colectomy in patients with active severe UC, even in the era of biologicals. Moreover, its effectiveness can be enhanced by concomitant immunomodulator therapy without compromising safety. CsA can be used as a "bridge" until the therapeutic effect of immunomodulators or biological therapy is fully developed. However, due to the high occurrence of AEs, tight patient monitoring during CsA therapy is needed.

Introduction

The development of anti-TNF agents has brought major advances in the treatment of ulcerative colitis (UC), however, many patients still require the use of 2^nd-, 3^rd-, or even 4^th-line biologicals or small molecules.

Aims & Methods

We conducted a retrospective, multicentre study with the inclusion of UC patients who failed anti-TNF therapy due to primary non-response (PNR) or loss of response (LOR), and received sequential biological treatment for moderate-to-severe disease activity or for acute, severe exacerbation (ASUC). The primary aim was to evaluate and compare the effectiveness of 2^nd-, 3^rd-, or 4^th-line biological or small molecule therapies after anti-TNF failure. Treatment effectiveness was determined by persistence and colectomy-free survival. Logistic regression analysis was performed to identify the predictive value of demographic factors, clinical, endoscopic, and laboratory parameters for colectomy.

Results

To date, 454 UC patients have been included. The median follow-up time was 57.7 months (IQR: 92.9-33.3). The indication for the 1^th-line anti-TNF therapy was chronic, refractory UC in 307(67.6%) and ASUC in 147(32.4%) patients. The rate of PNR, as reason for treatment discontinuation progressively increased in accordance with the lines of sequential treatment (23.1%/31.7%/36.2%/45.0%), however, the incidence of LOR did not show a definite tendency among the various therapeutic lines (50.0%/56.1%/58.0%/40.0%). A significant difference with treatment persistence was seen among the most frequently used biologicals and small molecules following anti-TNF failure (Table 1.). Ustekinumab (UST) had superior persistence compared to vedolizumab (VDZ) and tofacitinib (TOFA) at 3, 6, 12 and 24 months, regardless of the number of previous anti-TNFs. The overall colectomy rate was 15.6%, mostly due to chronic, refractory UC (61.9%). The probability of colectomy-free survival was 97.2%, 93.3% and 91.2% at 1, 2 and 3 years, respectively. Cyclosporine use during the course of the disease proved to be protective against colectomy (OR: 2.88, 95% CI: 1.447-5.733, p=0.0026). Pancolitis (OR: 3.24, 95% CI: 1.604-6.562, p=0.0012) appeared to be predictive for colectomy. Following anti-TNF failure, the incidence of colectomy was shown to be significantly lower with 2^nd-line UST (n=3 (5.8%), p=0.0422) than with VDZ (n=57 (16.8%)) or TOFA (n=11 (20.4%)).

Conclusion

According to the preliminary results of this ongoing cohort, sequential therapy was effective in avoiding colectomy in 84.4% of the patients and even after multiple lines of treatment we could expect a relatively low rate of colectomy. UST, as a 2^nd-line therapy after anti-TNF failure, was significantly superior, both in terms of persistence and colectomy-free survival, compared to VDZ or TOFA. Cyclosporine use reduced the risk of colectomy, while pancolitis was seen to be a predictive factor for surgery. Further analysis are being performed to identify factors that influence the efficacy of non-TNF agents and to clarify their role in the subsequent therapeutic lines.

Introduction

Colonoscopy plays a crucial role in management of ulcerative colitis (UC) that helps to assess mucosal healing. Different scoring systems are available to assess severity, however most of them do not correlate with disease extent.

Aims & Methods

Our study aimed to assess the predictive value and accuracy of PanMayo score compared to MES, UCEIS and Dublin in mid- and long-term disease outcomes. This is a retrospective, two-center study. UC patients, who underwent colonoscopy due to any reason between 2016 and 2018, were consecutively enrolled. PanMayo, MES, UCEIS and Dublin scores were recorded with clinical and demographical data at baseline. Disease flare, need for change in therapy (incl. initiation of biologicals, need for systemic steroids), hospitalisations and colectomy were collected during an at least 3-years follow-up. Patients were stratified by using baseline clinical activity (pMayo>1). Log-rank, logistic regression and Chi² tests were used to analyze outcomes and Kaplan Meier curves were plotted.

Results

A total of 250 UC patients (Table 1.) were enrolled. 157 (male ratio 0.49; mean age 46 IQR 19.5 years) UC patients had clinical remission, while 93 had active disease at baseline (male ratio 0.43; mean age 42 IQR 25 years). PanMayo, MES, and Dublin scores were positively associated with risk of flare-up (p=0.002; p<0.01; p=0.003). Increasing MES score was coupled with risk of relapse. PanMayo score (above 12 points), but not MES or UCEIS, was associated with the need of new biological (p<0.001) and treatment escalation (p=0.018), similar trend was found for the Dublin score for need for new biologicals in the remission cohort. All scores were strongly associated with the need for systemic steroids in patients with baseline remission. In the cohort with active disease at baseline, PanMayo (p=0.016) and Dublin (p=0.009) scores were associated to colectomy risk.

Table 1. Baseline demographic and clinical characteristics of patients

Conclusion

Our study suggests that combined endoscopic assessment of the extent and severity may be more precise in predicting disease outcomes in UC. PanMayo score may be an alternative of the existing scoring systems and was associated more granularly with disease outcomes.

Disclosure

There are no conflicts of interest to disclose.

Introduction

Approximately 10-15% of patients with Crohn's Disease (CD) experience penetrating complications during disease course, which significantly burdens patients' lives and impacts the healthcare system. Efficacy and safety of adipose-derived mesenchymal stem cell (MSC) transplantation (darvastrocel) in treating CD complicated by complex perianal fistulas are contradicting and real-world data are lacking.

Aims & Methods

Our study aimed to assess the effectiveness and safety of MSC therapy in managing perianal Crohn’s disease. This was a retrospective, multicenter cohort study enrolling CD patients with perianal fistulas. Baseline is defined as the day of MSC treatment while the follow-up is set at 6 to 12 months. Primary outcome was perianal clinical remission at w26 (defined by closure of all external openings), while secondary outcomes were clinical response rate, perianal clinical activity (defined by Perianal Disease Activity Index [PDAI]), and adverse events. Demographic, clinical, and surgical data were recorded at baseline, w12, w26, and at w52. Predictors of treatment failure were analyzed by logistic regression models.

Results

Overall, data of 69 patients (male/female ratio was 0.52 and median age was 36 [IQR 31-44]) were analyzed with a median follow-up duration of 52 [IQR 48-53] weeks. Perianal clinical remission was achieved in 49.3% until w26 and 44.9% (intention-to-treat) and 53.44% (per protocol) until w52, while baseline PDAI (OR 0.77, p = 0.043) score was associated with treatment failure. Characteristics of perianal fistulas were not linked to primary outcome. Clinical response rates were 69.6% at w26 and 78.3% (intention-to-treat) and 74.1% (per protocol) at w52. PDAI scores were decreased to w52 (5.2 [±3.1] to 3.2 [±2.8], p < 0.001). Worsening of perianal symptoms were not recorded, while improvement was reported in 78.8%, 81.1%, and 85.7% of cases at w12, w26, and w52. Total adverse events occurred in 8.7%, which were needed surgical reintervention. Furthermore, emerging stenosis, anal incontinence and severe infection were not registered.

Table 1. Baseline demographic and clinical characteristics of enrolled patients

Conclusion

Efficacy data are consisted with the registration ADMIRE study, more than 80% of patients benefit from the treatment, however the appearance of spontaneous closure is high in the literature. The safety profile is reassuring, and patients’ satisfaction is high.

Introduction

Bowel urgency is one of the most bothersome symptoms of ulcerative colitis (UC) and have a great impact on quality of life and psychosocial function. The Urgency Numerical Rating Scale (U-NRS) is desinged to ojectify this subjective symptom. It measures the degree of faecal urgency experienced over the past 24 hours by patients with UC on a scale of 0-10. We assumed that the scale has a large variance, as patients evaluate their own symptoms differently, the urge may be different quality for two patients with the same score.

Aims & Methods

The objective of our study was to investigate the possible components of urgency and refine the assessment of urgency. Patients with UC older than 18 years treated at our departments for at least 3 months and having complaints were enrolled in our study. The patients filled out our non-validated questionnaire with questions about fecal urgency (U-NRS), pain level, speed of urge, incontinence and lifestyle characteristics associated with incontinence. Statistical analysis was performed using STATA 18 program.

Results

263 patients were enrolled, median age was 39.5 years, the mean of disease duration was 11.7±9.2 years. The mean U-NRS score was 3.2±3.2, 32% (84/263) had 0 score and 3% (9/263) has 10 score. 12% of the patients (n=31) felt most difficult to hold mucus, 37% (n=97) stool and 29% (n=76) other secretions. 8% (n=22) had urge with every stool in the last 24 hours, 36% (n=95) had less than half of defecations. The speed of urge defined more the level of urgency than the pain level (R2=0.798 p<0.001, β=0.894 vs R²=0.805, p<0.001, β=0.117). The duration of faeces holding in the last 7 days had significant connection to U-NRS (R²=0.211, p<0.001, β=-0.46). Patients using public restroom at least once during the last week had significantly higher score on U-NRS than other patients (4.6±3.1 vs 2.4±3 p<0.001). 12% (31/263) used diaper. The usage of diapers was also significantly more often in patients with higher U-RNS score (5.2±3.2 vs 2.9±3.1,p<0.0001). Faecal leakage both during the day and night was significiantly higher with higher U-NRS score (p<0.001 for both). Patient reported outcome (PRO2) had a weak correlation with U-NRS (R²=0.14). However if we examine bloody stool, the stool number and difficulty of faecas holding seperately we got a significant and better correlation with urgency (R²=0.43). Patients with moderately severe-severe disease (PRO2 > 5) had a higher chance to have urgency (AUC=0.9). The possibility was higher to have urgency among patients with painful defecation (R²=0.41). The level of urgency, duration of faeces holding and the frequency of faeces holding problems had the strongest correlation with U-NRS (R²=0.83). Patients defined urgency with these parameters according to this result. We created score with them, level of urgency points + half of duration points + frequency, which showed a good model to refine the definition of urgency (R²=0.83).

Conclusion

Bowel urgency affects UC patients' lives and is associated with more severe disability. Bowel urgency is common in UC affecting about two-third of patients and associates with more severe activity of UC. Fecal urgency can characterize with the level of urgency, duration of faeces holding and the frequence of stool more accurately than a single, subjective numeric scale. A new scoring system is needed to more accurately assess patients' complaints in this area and to objectify severity.

Disclosure

The authors have no potential conflict of interest to disclose

Introduction

Ustekinumab has been shown to be effective in the treatment of UC. Data on its effectiveness in clinical practice are needed both in the short and long term.

Aims & Methods

Primary aim: To assess the durability 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.
Methods: Retrospective, multicenter study including UC patients who had received the 1^st ustekinumab dose at least 16 weeks before inclusion. Patients were followed-up from the 1^st ustekinumab dose to treatment discontinuation or last visit. 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 not in remission at subsequent time points (negative imputation).

Results

620 patients with UC were included, 57% with extensive colitis, 95% exposed to biologics (mean number of biologics 2), and 25% to tofacitinib. 78% of patients who started ustekinumab maintenance treatment, did it with 90 mg every-8-weeks dose. 155 patients (25%) withdrew ustekinumab during follow-up [median=12 months (m)]. Incidence rate of ustekinumab discontinuation was 20% per patient-year of follow-up. The probability of maintaining ustekinumab was 78% at 1 year and 68% at 2 years. Among patients who withdrew ustekinumab, the main reasons were primary non-response (39%) and loss of response (35%). Anaemia at baseline (HR=1.5, 95%CI=1.1-2.1), steroids at baseline (HR=1.5; 95%CI=1.06-2.08), and more severe clinical activity at baseline (HR=1.5; 95%CI=1.09-2.06) were associated with higher risk of ustekinumab discontinuation. At the end of the induction (week 16), 226 (40%) patients were in steroid-free remission; 11 (20%) patients were in steroid-free remission at week 4, and 191 (34%) at week 8. In the long-term, the proportion of patients in steroid-free remission was 50% at 1 year, 49% at 2 years and 49% at 3 years. Moderate-severe vs. mild disease activity at baseline (OR=0.3, 95%CI=0.2-0.5), male sex (OR=0.5; 95%CI=0.4-0.8), and increased number of previous biologics (OR=0.6, 95%CI=0.6-0.8) were associated with lower likelihood of steroid-free remission at week 16. A total of 57 (25%) patients among those with active disease at baseline and with steroid-free remission at week 16, lost response during a median follow-up of 8 m (IQR=3-16 m); 75% of patients maintained effectiveness at 1 year, and 57% at 2 years. The dose was escalated in 72% of patients with loss of response, and 80% improved (67% remission); an intravenous reinduction was given in 3 patients, and none of them improved. A total of 176 patients (28%) had at least one adverse event, with infections being the most frequent (11%). No negative impact on extraintestinal manifestations and/or immunomediated diseases was seen.

Conclusion

Ustekinumab was effective in inducing remission even in highly refractory UC patients. A proportion of patients discontinued the treatment, mostly due to primary failure and loss of response. Dose escalation may be effective to regain response after loss of effectiveness. The safety profile was consistent with previous studies.

Disclosure

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

Introduction

Crohn’s disease (CD) complicated with intra-abdominal abscess often requires surgical intervention. Image guided percutaneous drainage (PD) can help to avoid surgical interventions, however there is limited evidence on the optimal management after PD.

Aims & Methods

Our study aimed to analyze the long-term outcomes of CD complicated with intra-abdominal abscess after intervention. In this multicenter, interational retrospective trial penetrating CD patients with simplex intra-abdominal abscess were enrolled and followed until 12-24 months. Baseline was the day of the first detection of abdominal abscess. Patients with urgent resection were excluded. Patients were grouped based on elective surgical need during follow-up after a successful PD, while the control group consisted of patients who underwent resection without PD. Primary outcome was the abscess recurrence, while stoma rate, post procedural complications rate (<30 days), need for re-drainage and postoperative luminal recurrence were analyzed as secondary outcomes.

Results

A total of 151 CD patients from 9 countries were recruited and 86/151 patients had PD due to simplex abdominal abscess (Table 1.). Abscess recurrence rates were similar (12.8% vs. 7.7%, p=0.231). Need for re-drainage was more common amongst PD patients (OR=0.088, 95% CI=0.011-0.682), while hospital admission need was more frequent in control patients (OR=2.56, 95% CI=1.22-5.37). Postoperative luminal recurrence, new stoma, and biological treatment escalation needs were similar between groups based on PD. Surgical complications were coupled with increased odds in patients without prior PD (OR=3.3, 95% CI=1.09-10.0), septic complications, perforation and new fistula formation were reported the most, while PD associated complication did not occur. Higher baseline diameter of the abscess increased the odds for postoperative recurrence (OR=1.05, 95% CI=1.02-1.08) and new biological treatment initiation (OR=0.98, 95% CI=0.96-0.98). Elective resection was delayed after PD compared to control (24 vs 10 week, p=0.003). Time until resection increased the odds for redrainage (OR=1.03, 95% CI 1.01-1.05), and outcome was worse exceeding 17 weeks.

Conclusion

The size of the abscess determines the outcomes, while surgical treatment alone may be associated with post-procedural complications. PD may delay resection; however, this delay can necessitate re-drainage.