Introduction

Personalized therapy offers great potential to improve disease outcomes. To this end, identifying different subsets of patients according to their disease prevalence may be helpful in building therapeutic strategies. Unlike Crohn's disease (CD), ulcerative colitis (UC) is highly variable in response to treatments, including biologic agents (1). UC patients may be stratified according to distinctive cytokine profiles, excluding classical pro-inflammatory cytokines such as TNF-α and IL-6. We hypothesized that clarifying this difference in cytokine profile would help optimize therapeutic strategies.

Aims & Methods

To prove this hypothesis, both helper T-cell (Th) cytokine profiles of UC patients and HLA genotyping, which may have caused differences in immune responses, were analyzed. In this study, in a cohort of clinically and endoscopically diagnosed UC patients and/or healthy control subjects (HC) and CD patients, blood samples were examined for Th cell profiles (Th1, Th2, Th17, Treg (regulatory T cell)) and HLA typing by surface chemokines.

Results

Sixty-two patients with UC [male/female 40:22, mean age 51.1 years (22-80), mean disease duration 14.74 years (2 months-54 years), disease distribution; 11 proctitis, 18 left-sided colitis 31 cases with pancolitis and 2 other cases (right-sided colitis and local type)] were analyzed with full informed consent. Most of the UC patients were in clinical remission (8/62 active), and 31 patients had current or previous steroid use, including 1 resistant case and 23 dependent cases. Sixteen UC patients were treated with biologics (4 patients with infliximab, 1 patient with golimumab, 1 patient with adalimumab, 2 patients with ustekinumab, 1 patient with vedolizumab, and 4 patients with tofacitinib). Compared to CD and HD, UC was characterized by significantly higher Th2 and Treg low (p<0.05). UC was divided into high and low groups with a Th2/Treg ratio of 1.0. Those with a higher Th2/Treg ratio had significantly longer disease duration (18.91±12.45 vs 12.58±9.84, p=0.04) and tended to use steroids/immunosuppressants more frequently (66.7% vs 48.5%, p=0.26). Moreover, such aberrant immune responses were derived from HLA typing, but interestingly, a characteristic HLA bias oriented toward lower Th2/Treg ratios (DRB1*15:02:01, DQB1*06:01:01, DPB1*09:01) (40.0% vs 78.5% , p=0.05; 92.8% vs 40.0%, p=0.02; 40.0% vs 78.5%, p=0.05).

Conclusion

Cytokine assessment may help identify patient subgroups that may benefit from therapeutic approaches that modulate Th2 cytokines. However, disease pathophysiology is not necessarily correlated with genetic factors, and various causes such as intestinal microbiota must also be considered.

References

1. Aliment Pharmacol Ther. 47(2):162-175, 2018.

Disclosure

The authors, Hidekazu Suzuki, received the reserach grant from Biofermin Pharm. Co., and the lecture fee from Astellas Co., Otsuka Pharm. Co., EA Pharma Co., and Takeda Pharm. Inc.

Introduction

In Japan, the Ministry of Health, Labor, and Welfare (MHLW) registered all patients with ulcerative colitis (UC) from 2003 to 2014, and real-world data (RWD) are available in a national database. Deep learning models have been used to analyse RWD, but visualising the relationship between outcomes and explanatory variables is difficult.

Aims & Methods

Therefore, in this study, we used explainable artificial intelligence (AI) to calculate the regression coefficient for each parameter to determine the explanatory variables involved in steroid-resistant UC and constructed a model to predict steroid-resistant UC at the time of a patient's first visit. We obtained data on all patients with UC newly registered in the MHLW database between 2003 and 2011 (before the spread of biologics in Japan). Of the 79,096 patients identified, 4,003 who had three years of data, a Mayo score of 3 or higher at the first visit, and who had been using steroids from the time of the first visit were included in the analysis. For explainable AI, a point-wise linear model (PWL) was used to generate a custom-made logistic regression model for each case. Clustering analysis was performed based on the similarity of the coefficients (weights) of these logistic regression models. Finally, the association with outcomes was evaluated by analysing the weights of factors with a significant difference (p<0.01) between the clusters.

Results

The area under the curve (AUC) of the PWL model was 0.628 for the training set and 0.627 for the test set. The likelihood ratio was 1.36. By clustering, the analysed population was classified into two groups (S group, predicted to be in remission after three years: 2,040 cases; R group, predicted not to be in remission: 1,963 cases). In both groups, female sex (R group: median weight 0.0027), positive stool culture (R group: median weight 0.0041), and colonic mucosal abnormalities (R group: median weight 0.0113) had a strong relationship with steroid resistance. The R group tended to have significantly higher frequencies than the S group. In the R group, pseudopolyposis (median weight = 0.0351), caecal lesions (median weight = 0.024), CRP (median weight = 0.0163), ascending colon lesions (median weight = 0.0133), and transverse colon lesions (median weight = 0.0107) were observed. Conversely, the white blood cell count (S -0.0021 vs R -0.0037), frequency of defecation (S -0.0053 vs R -0.0055), bloody stool (S -0.0021 vs R -0.0016), stool form (S -0.0347 vs R -0.0367), and abdominal pain (S -0.0291 vs R -0.0383) were not significantly related to steroid resistance in both groups.

Conclusion

Explainable AI in a national database with three years of records allowed us to build a predictive model for refractory UC. Female sex, positive faecal bacterial cultures, colonic mucosal abnormalities, and lesions extending into the right colon were important predictors of steroid resistance. Understanding the predictors of steroid resistance and dependence at the time of steroid introduction, based on national data before the spread of biologics, can facilitate prompt and timely treatment plans for patients with UC.

References

Kanatani et al. Biology 11:951, 2022.

Disclosure

The authors, Hidekazu Suzuki, received the reserach grant from Biofermin Pharm. Co., and the lecture fee from Astellas Co., Otsuka Pharm. Co., EA Pharma Co., and Takeda Pharm. Inc.

Introduction

Severe acute colitis (SAC) is a life-threatening complication of inflammatory bowel disease (IBD), particularly ulcerative colitis, This requires immediate treatment with intravenous corticosteroids. Patients who are likely to fail treatment with a first-line approach need to be identified early in order to expedite second-line therapy or surgery.

Aims & Methods

This study aimed to evaluate the prognostic performance of the Ho score(day1), the Oxford score (day 3), and the CRP/albumin ratio in predicting corticosteroid response in SAC.
This was a retrospective, single-center analytical study including all patients hospitalized for SAC in a north african gastroenterology department. Clinical and biological data were collected at admission and on the third day of corticosteroid therapy. The Ho score was based on three criteria: CRP > 100 mg/L, albumin < 30 g/L, and > 8 stools/day (positive if ≥ 2). The Oxford score was considered positive on day 3 in cases of > 8 stools/day or ≥ 3 stools with CRP > 45 mg/L. The CRP/albumin ratio was analyzed with a cut-off value of 3.0. Corticosteroid response was defined as clinical improvement without rescue therapy or surgery. Statistical analysis included Chi² test for associations, Student’s t-test for comparing means, and calculation of diagnostic performance (sensitivity, specificity, positive and negative predictive values).

Results

Forty-three patients were included. The mean age was 35.5 years (range: 18–58), with a female-to-male ratio of 2:1.
SAC was inaugural in 25 patients (58.1%), while 18 patients (41.9%) had a known history of IBD.
The overall corticosteroid response rate was 44.2%.
The Ho score was positive in 26 patients, with a response rate of 15.4% versus 56.7% for negative scores (p = 0.030). Its diagnostic performance was modest: sensitivity 10.5%, specificity 54.2%, positive predictive value (PPV) 15.4%, and negative predictive value (NPV) 43.3%.
The Oxford score was positive in 31 patients, with a response rate of 29% compared to 83.3% in the negative group (p = 0.004). It showed higher sensitivity (47.4%) but lower specificity (8.3%), with a PPV of 29.0% and NPV of 16.7%.
The CRP/albumin ratio was significantly higher in non-responders (3.86 vs. 2.30; p = 0.038). When using a cut-off of 3.0, this marker had a sensitivity of 15.8%, specificity 29.2%, PPV 15.0%, and NPV 30.4%.

Conclusion

The Oxford score, despite low specificity, showed the best performance in identifying patients at risk of corticosteroid failure by day 3. The Ho score, though less sensitive, remains useful at admission for early risk stratification. The CRP/albumin ratio, while simple and biologically relevant, demonstrated limited predictive performance at the fixed threshold of 3.0. Further studies are needed to refine these tools or develop composite models for early decision-making in SAC.

Introduction

Targeting interleukin (IL)-2 and its ability to expand regulatory T cells (Treg) represents a novel therapeutic mechanism for the treatment of ulcerative colitis (UC). Low-dose recombinant IL-2 (aldesleukin) has shown disease-modifying activity in UC in early clinical studies.^1,2 However, low dose IL-2 has a small selectivity window for Treg over conventional CD4+ T cells (Tcon) and natural killer (NK) cells, with the potential for inflammatory cell expansion and adverse events (AE) related to low selectivity. Efavaleukin alfa is an IL-2 mutein Fc fusion protein with a mutation that decreases binding to IL-2Rβ and increases dependence on IL-2Rα (CD25), which is expressed constitutively at high levels on Treg. Here we evaluated the selectivity of efavaleukin alfa for Treg expansion, using data from preclinical³ and phase 1 (NCT03451422)⁴ studies to support the biologic rationale for a phase 2 clinical study of efavaleukin alfa in UC patients.

Aims & Methods

In vitro activity and selectivity were assessed according to levels of phosphorylated STAT5 (pSTAT5) and proliferation of Treg, Tcon, and NK cells in primary human peripheral blood mononuclear cells (PBMC) cultured with increased doses of efavaleukin alfa or aldesleukin. The in vivo effects on body temperature, C-reactive protein (CRP), proinflammatory cytokine production, and peripheral blood Treg, Tcon, and NK cell numbers were evaluated in cynomolgus monkeys after escalating single SC doses of efavaleukin alfa or 5 consecutive daily SC doses of aldesleukin. Safety, tolerability, and pharmacodynamics of efavaleukin alfa vs placebo were evaluated in a single-dose phase 1a study in healthy subjects and in a multiple ascending dose phase 1b study in patients with systemic lupus erythematosus (SLE).

Results

In human PBMC cultures, efavaleukin alfa led to a more selective Treg response (pSTAT5 and proliferation) than aldesleukin, with lower levels of IL-2 signaling observed in non-Treg (Tcon and NK) cells and proliferation of inflammatory cells only observed at higher doses of efavaleukin alfa vs aldesleukin. Dose-dependent expansion of FoxP3+ Treg in aldesleukin-treated cynomolgus monkeys was accompanied by increased body temperature and levels of CRP and IL-6. However, efavaleukin alfa stimulated Treg expansion with no increases in IL-6 and without significant effects on body temperature or CRP except at the highest dose, suggesting an increased therapeutic window compared with aldesleukin. In phase 1 studies, peak Treg expansion was observed at 8 days post-dose, and mean Treg levels remained above baseline through the end of the follow-up period. The mean peak increases in FoxP3+ Treg were 4.7-fold above baseline after a single dose administered to healthy subjects and 17.4-fold above baseline after multiple doses in SLE patients. In contrast, there were minimal changes in fold-change of Tcon, CD8+ T cells, B cells, or NK cells with efavaleukin alfa. In phase 1 studies, the most common AEs were mild-moderate (grade 1-2) injection site reactions, and no dose-limiting toxicities, treatment-related serious AEs, or deaths were reported.

Conclusion

Efavaleukin alfa is a novel IL-2 therapy that has an increased therapeutic window compared with aldesleukin. Preclinical and phase 1 results with efavaleukin alfa demonstrated highly selective expansion of Treg with minimal effects on pro-inflammatory immune cells. These findings support the rationale and design of an ongoing phase 2b study investigating the safety and efficacy of efavaleukin alfa induction therapy in patients with moderate to severe active UC (NCT04987307).

References

(1) Allegretti J, et al. Gastroenterology. 2021;160(3):S9-S10
(2) Rosenzwaig M, et al. Ann Rheum Dis. 2019;78:209-217
(3) Tchao N, et al. Blood. 2017;130(S1):696.
(4) Tchao N, et al. Ann Rheum Dis. 2022;81:1343-1344 [AB0432]

Disclosure

Farshid Firoozbakht, Nandita Sarkar, and Kevin Gorski are employees and stockholders of Amgen Inc. Nadia Tchao is a former Amgen employee and stockholder.

Introduction

We lack reliable biomarkers to identify patients with inflammatory bowel disease (IBD) at a greater risk of severe disease course. With emerging evidence that early step-down treatment in severe patients leads to better disease outcomes, alongside worries about overtreatment of mild patients, there is a clinical need to identify such biomarkers.

Aims & Methods

In this study, we explore genetic variants associated with severe disease course for ulcerative colitis (UC) in a nationwide cohort of 4491 patients from Denmark.
We genotyped 4491 patients with UC (4153 from Danish birth blood spot archive; 338 from NorDIBD regional cohort), linking them with registry data capturing medical interactions throughout patients’ lifetimes. Patients who required 2+ IBD-related hospitalizations, 2+ IBD-related major surgeries, 1 IBD-related hospitalization and 1 IBD-related major surgery or use of systemic corticosteroids (≥5000 mg) in the first 3 years of diagnosis were defined as severe. We conducted a genome-wide association study comparing severe patients (N=1203) to those with a less severe disease course (N=3288).

Results

The GWAS identified a signal within the HLA region, with the HLA-DRB1*01:03 allele driving the association (OR=3.30 [2.23-4.87], P=2.08×10^-9, UC carriage rate=2.8%). We did not observe an association with CD severity in a similarly ascertained cohort of 3688 individuals (P=0.79).
Remarkably, carriage of DRB1*01:03 was associated with a seven-fold increase of major surgery risk (OR=7.05 [4.55-10.91], P=2.31×10^-16) (Table 1). At the point of diagnosis, carriage of DRB1*01:03 was associated with higher CRP levels (β=2.68, P=1.70×10^-7), f-cal levels (β=1.92, P=4.42×10^-3) and a higher rate of hospitalization at diagnosis (OR=1.64, P=0.014), suggesting that the effect on severity is not limited to disease progression.

Conclusion

In this large-scale, unselected nationwide cohort study, we find that HLA-DRB1*01:03 is a biomarker of UC disease course that is associated with a more severe presentation at diagnosis, as well as higher subsequent risk of surgery and hospitalization. Demonstrating the association at a genome-wide significance level for the first time, this study revitalizes findings from smaller studies at the beginning of the genetic era which explicitly recruited severe patients and made estimating carriage effects difficult.
While HLA-DRB1*01:03 is a low-frequency allele, patients who carry it are at a much higher risk of severe UC. As the cost of typing a single HLA allele is low (under 50 EUR) and several pharmacogenetic variants are beginning to be tested at diagnosis, we argue that it is a valuable addition to the arsenal of personalized healthcare tools.

Introduction

Acute Severe ulcerative colitis (ASUC) is a life-threatening medical emergency of colonic inflammatory bowel disease (IBD). Corticosteroids remain the primary initial therapy, although one-third of patients do not respond to treatment. In this perspective, early identification of steroid non-responsive ASUC patients is the key to an effective management and thus, a better prognosis.

Aims & Methods

The aim of our study was to evaluate the impact of CRP/albumin ratio measured on day 3 on treatment outcomes and disease course in ASUC. We conducted a retrospective descriptive study including patients who presented with ASUC over a 10-year period [January 2010 - December 2019]. The diagnosis of ASUC was established on Truelove and Witts criteria and supported by endoscopic findings. Patients demographics were collected; C-reactive protein (CRP) and albumin levels were recorded at baseline and during admission. Data were entered and analyzed by SPSS software version 26.

Results

We included 54 patients with a sex ratio of M/F=0.71. The mean age at diagnosis of IBD was 41.48 years [12-58]. A family history of IBD was noted in 13% of the patients. Twenty-seven patients had Ulcerative Colitis and 27 patients had Crohn´s disease. ASUC was inaugural of the disease in 35% of the patients. For the diagnosis of ASUC, the median number of bloody stools was 7 and the mean CRP level was 91 mg/L. At day 3 of first-line treatment with corticosteroids, the median number of bloody stools was 1 and the mean CRP level was 49 mg/L. First-line treatment failure was noted in 40% (n=20) of the patients with a mean duration of 8 days [3-20]. The mean level of the CRP/albumin ratio on day 3 was 1.8 [0.8-2.9]. Area under the receiver operating characteristic curve analysis showed that this ratio measured on day 3 was highly predictive of steroid non-responsiveness (AUROC=0.69, p=0.02). The optimal cutoff value was 1.6 (sensitivity, 80%; specificity, 57%). There was no significant linear association (Spearman r=-0.11, p=0.64) between this ratio and the timeframe of corticosteroids failure. A significant association was noted between this ratio and the urge to a rescue medical therapy (p=0.015) without being predictive of response (p=0.327). If on day 3, the ratio was higher than 1.6 and bloody stool frequency was beyond 3, the relative risk of steroid non-response was significantly raised at 3.85 (p<0.001) versus 1.7 if only a ratio above 1.6 was considered. As for longer prognosis, this ratio was higher in patients who underwent colectomy within a year of ASUC, without a significant association (n=13, p=0.07), and no correlation was noted with ASUC recurrence (p=0.23).

Conclusion

Our study showed that CRP/albumin ratio on day 3 is not only an effective predictor of non-response to steroids in ASUC, but also predicts the disease course beyond this severe flare-up.

Introduction

Urotensin II (U-II) is a vasoactive peptide whose interaction with its specific receptor (UTR) plays a key role in promoting several phlogistic pathways in different inflammatory-related diseases, including ulcerative colitis (UC). The incidence of UC is increasing worldwide, becoming a contemporary important health and socio-economic problem due to the burden of optimal medical management, especially in the acute severe UC (ASUC) setting. In the ASUC, in fact, the main goals for the clinicians at the moment of admission are represented by the rapid severity assessment and risk stratification to make the best therapeutic choice.

Aims & Methods

We aimed to assess the relationship between UTR expression and clinical, endoscopic, and biochemical severity of UC, exploring its predictivity predictive role for intravenous (iv) steroid administration therapeutic outcome. One-hundred patients receiving the first diagnosis of UC and 44 healthy subjects receiving a colorectal cancer screening colonoscopy were consecutively enrolled. UTR expression was assessed by quantitative polymerase chain reaction (qPCR), Western Blot (WB), and immunohistochemistry (IHC). Clinical, endoscopic, and histology activity of UC were evaluated by using Truelove and Witts (T&W) severity index, Mayo Endoscopic Score (MES), Truelove and Richards Index (TRI), Partial Mayo score (PMS) and Full Mayo Score (FMS). The “Albumin, C-reactive protein, Endoscopy” (ACE) index was also determined as a well-known score in the prediction of steroid response. Response to treatment was defined by combining bowel movements frequency and PCR levels according to the clinical practice guidelines.

Results

The UTR expression resulted higher in the lesioned mucosa of UC patients in comparison to healthy subjects (p <0.0001 all). A direct relationship between UTR (mRNA and protein) expression and disease severity assessment (T&W, TRI, MES, PMS, and FMS) was highlighted (p<0.0001 all). Of 100 patients, 72 presented ASUC requiring iv steroid administration. UTR expression (mRNA and protein) was higher in these individuals than in those (28/100) who underwent alternative medications (budesonide, 5-aminosalicylic acid, and others) (p<0.0001). Of 72 steroid-treated patients, 40 were considerable responders. The 32 steroid-non-responders showed an increased UTR expression (WB, IHC, and qPCR from lesioned mucosa), compared to the 40 steroid responders (p:0.0002, p:0.0001, p<0.0001 respectively). Logistic regression analysis revealed the UTR expression levels associated with the negative iv. steroids administration therapeutic outcome (p<0.05).
ROC curves for the prediction of negative iv steroid therapeutic outcome were generated for IHC (AUC: 0.93, 95% CI: 0.86-0.99, p<0.0001), WB (AUC: 0.94, 95% CI: 0.87-1.00, p<0.0001), qPCR from lesioned samples (AUC: 0.99, 95% CI: 0.97-1.00, p<0.0001) UTR expression. The diagnostic performance of qPCR-UTR was superior to the ACE index (AUC: 0.94, 95% CI: 0.88-0.99) in the prediction of steroid response.
Finally, all the steroid responder patients (40/100) were undergone a second colonoscopy after one month and were considered “full responders” because of the reduction of at least two points of the continuous FMS in comparison to the baseline value.

Conclusion

UTR represents a promising inflammatory marker related to clinical, endoscopic, and histology disease activity as well as a predictive marker of steroid administration therapeutic outcome in the UC context.

References

1. Brancaccio D, Merlino F, Limatola A, et al. An investigation into the origin of the biased agonism associated with the urotensin II receptor activation. Journal of peptide science: an official publication of the European Peptide Society. 2015;21(5):392-399.
2. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nature reviews Gastroenterology & hepatology. 2015;12(12):720-727.
3. Ho GT, Mowat C, Goddard CJ, et al. Predicting the outcome of severe ulcerative colitis: development of a novel risk score to aid early selection of patients for second-line medical therapy or surgery. Alimentary pharmacology & therapeutics. 2004;19(10):1079-1087.
4. Gravina AG, Dallio M, Tuccillo C, et al. Urotensin II receptor expression in patients with ulcerative colitis: a pilot study. Minerva gastroenterologica e dietologica. 2020;66(1):23-28.