Introduction

Mirikizumab (miri), an anti-IL-23p19 antibody, demonstrated efficacy and safety in patients with moderately-to-severely active ulcerative colitis (UC) in the Phase 3 LUCENT-1 induction¹ (NCT03518086) and LUCENT-2 maintenance² (NCT03524092) trials. Bowel urgency (BU) remission and clinically meaningful improvement (CMI) are associated with clinical response and remission.³ This analysis evaluated if the addition of BU improvement to the achievement of clinical response or remission was associated with better quality of life (QoL).

Aims & Methods

In LUCENT-1, patients were randomized 3:1 to miri 300mg intravenous or placebo every four weeks. Miri-treated patients achieving clinical response to miri at week 12 (W12) were re-randomized 2:1 to subcutaneous miri 200mg or placebo Q4W for 40 weeks in LUCENT-2 (continuous treatment up to W52). Clinical remission is based on the modified Mayo Score (MMS) and was defined as: stool frequency subscore = 0 or 1 with a ≥1-point decrease from baseline; rectal bleeding (RB) subscore = 0; endoscopic subscore = 0 or 1. Clinical response was defined as ≥2-point and ≥30% decrease in the MMS from baseline, and RB = 0 or 1, or ≥1-point decrease from baseline. Patients’ QoL was measured using the Inflammatory Bowel Disease Questionnaire (IBDQ): IBDQ response (≥16-point improvement from baseline in IBDQ total score) and IBDQ remission (IBDQ total score ≥ 170; higher scores indicating better disease specific QoL).^4,5 BU was assessed using the Urgency Numeric Rating Scale (UNRS), an 11-point scale ranging from 0 (“no urgency”) to 10 (“worst possible urgency”), with both BU CMI (≥3-point change) and BU remission (UNRS score of 0 or 1), measured in patients with a baseline UNRS of ≥3.⁶ The association between BU improvement (CMI or remission) and IBDQ (response or remission) was evaluated using the chi-square test of association among patients with baseline UNRS ≥3 who achieved clinical response. This analysis was repeated among patients who achieved clinical remission.

Results

Among patients achieving clinical response, a significantly higher proportion achieved IBDQ response and IBDQ remission when they also achieved BU CMI or BU remission compared with those who did not both at W12 and W52 (p<0.005) (Table 1). Among patients who achieved clinical remission, achievement of BU CMI was significantly associated with IBDQ response (p<0.005) but not IBDQ remission, and achievement of BU remission was significantly associated with IBDQ remission (p<0.005) but not IBDQ response at W12; achieving BU remission was significantly associated with better IBDQ response and IBDQ remission at week 52 (p<0.05).

Table 1. Association of Clinical Remission and Response with achievement of Bowel Urgency Remission and CMI on IBDQ Response/Remission in patients with UC at W12 and W52 of Continuous Treatment

Conclusion

Among patients with UC from miri phase 3 trials, the additional improvement of BU (CMI or remission) to the achievement of clinical response or remission was associated with greater QoL assessed by IBDQ response and remission.

References

1. D’Haens, G., et al. "OP26 Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 LUCENT-1 study." Journal of Crohn's and Colitis 16. Supplement_1 (2022): i028-i029.
2. Dubinsky, M. C., et al. "867e: Efficacy and safety of mirikizumab as maintenance therapy in patients with moderately to severely active ulcerative colitis: results from the phase 3 LUCENT-2 study." Gastroenterology 162.7 (2022): S-1393.
3. Dubinsky, M.C., et al. “Clinical Effect of Mirikizumab Treatment on Bowel Urgency in Patients with Moderately to Severely Active Ulcerative Colitis and the Clinical Relevance of Bowel Urgency Improvement for Disease Remission.” Crohn’s & Colitis 360, Volume 5, Issue 1, January 2023, otac044.
4. Irvine EJ. Quality of life of patients with ulcerative colitis: past, present, and future. Inflamm Bowel Dis. 2008;14: 554-565.
5. Irvine EJ. Development and subsequent refinement of the inflammatory bowel disease questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1999;28: S23-S27.
6. Dubinsky, M. C., et al. "P138 Psychometric validation and interpretation of a patient-reported outcomes instrument to assess bowel urgency among adults with moderate to severe Ulcerative Colitis." Journal of Crohn's and Colitis 16. Supplement_1 (2022): i220-i222.

Disclosure

David T. Rubin receives grants or contracts from Takeda, and discloses consultancy fees with Abbvie, Altrubio, Allergan, Inc., American College of Gastroenterology, Arena Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Ltd., Bristol-Myers Squibb, Celgene Corp/Syneos, Cornerstones Health, Inc. (non-profit), GalenPharma/Atlantica, Genentech/Roche, Gilead Sciences, GoDuRn, LLC, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen Pharmaceuticals, Eli Lilly and Company, Materia Prima, Pfizer, Prometheus Biosciences, Reistone, Takeda and Techlab, Inc. Jianmin Wu, Simin K Baygani, Nathan Morris, Theresa Hunter Gibble are employees of Eli Lilly and Company. Stefan Schreiber receives consultancy and/or personal fees from AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Ferring, Fresenius, Galapagos/Gilead, HIKMA, IMAB, Janssen, Lilly, MSD, Mylan, Pfizer, Prometheus, Takeda, and Theravance.

Introduction

The use of infliximab (IFX) is limited by low treatment persistence. Proactive therapeutic drug monitoring (pTDM) has been shown to increase the treatment persistence in inflammatory bowel disease (IBD) patients but the real-life data evaluating effectiveness, safety and costs of this approach are scarce.

Aims & Methods

The aim of this study was to assess survival on treatment, safety and costs of pTDM of IFX in the treatment IBD.
IBD patients who started IFX in a referral centre using pTDM between January 2018 and March 2021 were included. The main outcomes were treatment persistence, adverse events and incremental costs of pTDM.
IFX trough levels were assessed in the week 14 and subsequently every six months by commercially available ELISA kit (Ridascreen R-Biopharm) and the intensification of treatment the cut-off of 3μg/ml was used.
Costs related to the measurements of levels and the costs of intensified treatment were calculated. The costs of pTDM were compared costs of a modelled cohort using reactive TDM (rTDM) based on the data from the same cohort. The model used arbitrarily determined intensification regimen to 5mg/kg of IFX every 4 weeks in pharmacokinetically determined clinical or endoscopic loss of response. The calculation was performed for the first year of treatment.

Results

Overall, 99 patients with IBD were included (58 men – 59%; mean age 39,96 years, minimum-maximum, 20-73 years; 64% patients with Crohn´disease; mean disease duration 103 months, minimum – maximum, 8-402 months).
The treatment was intensified in 57 patients (58%). Overall treatment survival with pTDM was 87% at 6 months, 77% at one year, 66% at two years and 60% at both, the third and fourth year of treatment. There were no differences between patients on conventional regimen vs. intensified regimen with regards to adverse events.
The costs related to pTDM in this cohort of 99 patients were € 90 306,56 while the costs of the modelled cohort using rTDM were € 24 846,30. The overall incremental costs were thus € 65 460,26 with mean costs per patient for the first year of treatment of € 661,21.

Conclusion

Proactive TDM of IFX results in a steady 60% treatment persistence beyond the second year of treatment with no impact on the safety.
In the context of this solid treatment persistence, the incremental costs related to proactive TDM seem negligible when considering the costs of alternative biologicals used in case of loss of response to IFX.

Disclosure

nothing to disclose

Introduction

Mirikizumab (miri), an anti-IL-23p19 antibody, demonstrated efficacy and safety in patients with moderately-to-severely active ulcerative colitis (UC) in LUCENT Phase 3 trials.^1,2 Bowel urgency (BU) clinically meaningful improvement (CMI) and BU remission were associated with clinical response and remission and also contributed to the improvement in Work Productivity and Activity Impairment Questionnaire UC (WPAI:UC) scores.^3,4 This analysis evaluated if the addition of BU improvement to clinical response or remission was associated with better work productivity.

Aims & Methods

In LUCENT-1 (NCT03518086), patients were randomized 3:1 to induction miri 300mg intravenous or placebo every four weeks (Q4W). Patients who achieved clinical response to miri at week 12 (W12) were re-randomized 2:1 to maintenance subcutaneous injection of miri 200mg or placebo Q4W for 40 weeks in LUCENT-2 [52 weeks (W52) continuous treatment] (NCT03524092). Clinical response and remission were assessed along with change from baseline in WPAI:UC domain scores (activity impairment, absenteeism, presenteeism, and overall work impairment).⁵ BU was assessed using the Urgency Numeric Rating Scale (UNRS), an 11-point scale ranging from 0 (“no urgency”) to 10 (“worst possible urgency”), with both BU CMI (≥3-point change) and BU remission (UNRS score of 0 or 1), measured in patients with a baseline UNRS of ≥3.⁶ The association between BU (CMI or remission) with the change of WPAI:UC was evaluated using analysis of variance among patients with baseline UNRS ≥3 who achieved clinical response. This analysis was repeated among patients who achieved clinical remission.

Results

The addition of BU CMI was positively associated with reduction of activity impairment, presenteeism, and overall work impairment in patients who achieved clinical response or remission at both W12 and W52 (p<0.005) (Table 1). Achieving clinical response and BU remission was significantly associated with greater reduction of activity impairment, presenteeism, and overall work impairment compared to patients with clinical remission only at both W12 and W52 (p<0.01). The combined improvement of achieving both clinical remission and BU remission was significantly associated with higher reduction in activity impairment at W12 (-36.1% vs -27.3%; p=0.0147) and overall work impairment at W52 (-39.9% vs -29.8%; p=0.0394). Patients who achieved both clinical response or clinical remission and BU CMI or BU remission did not show a significant difference in absenteeism compared to those who achieved clinical response or remission alone.

TABLE 1. Association of Clinical Remission/Response with achievement of Bowel Urgency Remission/CMI on Change from Baseline of WPAI:UC Domain Scores in Patients with UC at W12 and W52 of Continuous Treatment
​

Conclusion

Among patients with UC from miri phase 3 trials, the addition of BU (CMI or remission) to the achievement of clinical response or remission was associated with reduction of WPAI:UC scores: activity impairment, presenteeism, and overall work impairment.

References

1. 1. D’Haens, G., et al. "OP26 Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 LUCENT-1 study." J Crohns Colitis 16. Supplement_1(2022):i028-i029.
   2. Dubinsky, M.C., et al. "867e: Efficacy and safety of mirikizumab as maintenance therapy in patients with moderately to severely active ulcerative colitis: results from the phase 3 LUCENT-2 study." Gastroenterology 162.7(2022):S-1393.
   3. Dubinsky, M.C., et al. “Clinical Effect of Mirikizumab Treatment on Bowel Urgency in Patients with Moderately to Severely Active Ulcerative Colitis and the Clinical Relevance of Bowel Urgency Improvement for Disease Remission.” Crohns Colitis 360, 5(1), (2023): otac044.
   4. Sands B.E., et al. “Relative association of bowel urgency clinically meaningful improvement and bowel urgency remission versus stool frequency remission and rectal bleeding remission with improvement in Work Productivity and Activity Scores in patients with moderately-to-severely active Ulcerative Colitis: An analysis from LUCENT-1 and LUCENT-2 phase 3 clinical trials.” J Crohns Colitis 17, Supplement_1(2023):i775–i777.
   5. Reilly Associates WPAI Scoring. Accessed March 28, 2022. http://www.reillyassociates.net/WPAI_Scoring.html
   6. Dubinsky, M.C., et al. "P138 Psychometric validation and interpretation of a patient-reported outcomes instrument to assess bowel urgency among adults with moderate to severe Ulcerative Colitis." J Crohns Colitis 16. Supplement_1(2022):i220-i222.

Disclosure

David T. Rubin receives grants or contracts from Takeda, and discloses consultancy fees with Abbvie, Altrubio, Allergan, Inc., American College of Gastroenterology, Arena Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Ltd., Bristol-Myers Squibb, Celgene Corp/Syneos, Cornerstones Health, Inc. (non-profit), GalenPharma/Atlantica, Genentech/Roche, Gilead Sciences, GoDuRn, LLC, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen Pharmaceuticals, Eli Lilly and Company, Materia Prima, Pfizer, Prometheus Biosciences, Reistone, Takeda and Techlab, Inc. Jianmin Wu, Bomina Park, Simin K Baygani, Nathan Morris, Theresa Hunter Gibble are employees of Eli Lilly and Company. Stefan Schreiber receives consultancy and/or personal fees from AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Ferring, Fresenius, Galapagos/Gilead, HIKMA, IMAB, Janssen, Lilly, MSD, Mylan, Pfizer, Prometheus, Takeda, and Theravance.

Clinical Case Summary

A 72 years old caucasian women with no relevant medical history presented to the emergency department with two weeks history of abdominal pain in the upper quadrants associated with fullness, vomiting and a significant weight loss and nighttime hypersweating. On physical examination, abdomen was painful on epigastric and periumbilical region. Analytically, hemoglobin 11.1g/dL, leukocytes 9200/mm3, platelet count 315000/μL, CRP 8.22mg/dL. Tests for HIV and EBV were negative. Computed Tomography (CT) of the abdomen and pelvis revealed stomach with thickened walls, densification of adjacent fat and heterogeneous adenopathies. She was admitted to the department of Gastroenterology for investigation. The upper gastrointestinal endoscopy revealed extensive neoplasia of the body and gastric antrum. Biopsies revealed gastric mucosa with infiltration by atypical lymphoid proliferation with a "starry sky" pattern suggestive of high-grade B-cell non-Hodgkin's lymphoma (NHL). FISH analysis revealed t(8;14) c-myc positive. Once morphological and immunohistochemistry feature favors Burkitt’s lymphoma, she was transferred to the department of Hematology. Patient was treated with a full dose CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) and 3 cycles of dose adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab). Complete remission was documented on positron emission tomography (PET).
Sporadic Burkitt's lymphoma is rare (1-2% of all lymphomas in adults), being one of the most aggressive forms of B-cell NHL. Primary gastric involvement is extremely rare. With the advancement of medicine and greater survival, we must consider this diagnosis, even in the absence of risk factors, atypical location and age group. This case emphasizes the importance of clinicopathological correlation and the importance of early diagnosis for immediate and aggressive intervention, fundamental in reducing morbidity and mortality.

References

1. Zhimin Bai, Yong Zhou. A systematic review of primary gastric diffuse large B-cell lymphoma: Clinical diagnosis, staging, treatment and prognostic factors, Leukemia Research,
Volume 111, 2021, 106716, ISSN 0145-2126, https://doi.org/10.1016/j.leukres.2021.106716.
2. Čubranić A, Golčić M, Fučkar-Čupić D, Brozović B, Gajski D, Brumini I. BURKITT LYMPHOMA IN GASTROINTESTINAL TRACT: A REPORT OF TWO CASES. Acta Clin Croat. 2019 Jun;58(2):386-390. doi: 10.20471/acc.2019.58.02.25. PMID: 31819338; PMCID: PMC6884372.
3. Usman A. Pirzada, Kishore Kumar, Hassan Tariq, Masooma Niazi, Jasbir Makker; Case of Gastric Diffuse Large B-Cell Lymphoma. Case Rep Oncol 6 May 2019; 12 (1): 39–46. https://doi.org/10.1159/000496332
4. Khan A, Khan S, Arshad U. Primary Gastric Burkitt's lymphoma. Pak J Med Sci. 2017 Sep-Oct;33(5):1294-1297. doi: 10.12669/pjms.335.13002. PMID: 29142583; PMCID: PMC5673752.

Clinical Case Summary

A 62 y/o male complaining from epigastric pain, constipation, vomiting and eructation for two months and CT abd revealed irresectable pancreatic head mass 4.5x4.5 cm encasing PV and SMV with duodenal invasion. Ryle decompression was done before EGD, duodenal obstruction was noted and biopsy showed duodenitis (stasis induced). EUS-FNB confirmed well differentiated AC. Duodenal stenting was successfully performed with improving symptoms.
After one week patient complained from weakness and abnormal gait, examination showed normal vital signs, bilateral lower limb edema and patient was lethargic. Three days after, the patient became confused (GCS 12), so he was admitted to ICU.
CT brain was unremarkable. Lab investigations showed the following:
Na 130, K 4.1, Ca 7.8, Phos 2.8, Mg 2.6, Alb 2.9
Refeeding injury was suspected and TPN was started by the ICU team. No improvement of the consciousness was achieved and patient caught chest infection, developed sepsis and died.
Discussion: Refeeding syndrome is a serious complication that can be easily missed [1] in upper GI malignant obstructions with prolonged decreased oral intake along with the malignancy cachexia status. These obstructions may need surgery or stenting to regain patency and without cautious monitoring of the nutrients repletion rate either enteral or parenteral this will lead to fluid and electrolyte disturbance (Fluid balance abnormalities, Abnormal glucose metabolism, Vitamin deficiency, e.g., vitamin B1 (thiamine), Hypophosphatemia, Hypomagnesaemia and/or Hypokalemia) [2] with symptoms ranging from vague up to life threatening conditions like disturbed conscious level and heart failure. Our patient had high risk of developing refeeding syndrome due to caloric deprivation secondary to duodenal obstruction with development of the symptoms after stenting and restarting oral intake.
Conclusion: Nutritionist counseling after GI stenting of upper GI malignant obstructions is needed to avoid refeeding syndrome.

References

[1] Reber, E., Friedli, N., Vasiloglou, M.F., Schuetz, P. and Stanga, Z., 2019. Management of refeeding syndrome in medical inpatients. Journal of clinical medicine, 8(12), p.2202.
[2] Crook, M.A., Hally, V. and Panteli, J.V., 2001. The importance of the refeeding syndrome. Nutrition, 17(7-8), pp.632-637.

Introduction

Pancreatic acinar cystic transformation (ACT) was first described in 2000. Its initially supposed pre-neoplastic nature was reconsidered in the WHO Classification 2019. Its current management prone to a non-surgical approach, and so rare cases of histopathological diagnosis have been obtained since. Radiological diagnostic criteria have been proposed to differentiate ACT from Branch-duct Intraductal Papillary Mucinous Neoplasms (BD-IPMN) (Delavaud et al., 2014): 1) ≥ 5 cysts, 2) clustered peripheral small cysts, 3) cyst calcifications and 4) no communication with the main pancreatic duct.

Aims & Methods

The aims of this study were to describe the clinical and radiological characteristics of patients with a presumed diagnosis of ACT in imaging and to assess the role of these known radiological criteria in case of possible differential diagnoses. In this single-centre retrospective study (2003-2021), consecutive patients with a presumed diagnosis of ACT in the coding database were included. Patients without an available imaging (CT or MRI) for expert radiological centralized review were excluded. A group of “typical” diagnosis of ACT was defined as the absence of differential diagnosis to be evoked. A group of “uncertain” diagnosis of ACT was defined as other possible differential diagnoses.

Results

A total of 64 patients were included (35 male patients [55%]). Median age of diagnosis was of 60 (IQR 47-67) years. ACT diagnosis was “typical” for 35 (55%) patients and was “uncertain” for 29 (45%) patients. In the “typical” group, 91.4% of patients presented ≥3 radiological criteria versus 96.6% in the “uncertain” group (p=0.61). There were more calcifications and <10 cysts in the “uncertain” group compared to the “typical” group (86% versus 66%, p = 0.041 et 24% versus 6%, p = 0.06, respectively). In the “uncertain” group, the main differential diagnoses suggested were: 16 (55%) BD-IPMN and 7 (24%) calcified chronic pancreatitis (CCP). A pathological confirmation of ACT was obtained for three patients from which two were in the “uncertain” group.

Conclusion

ACT displays an heterogenous morphological imaging presentation reflecting a challenge for accurate non-invasive diagnosis. The published diagnostic radiological criteria seem not to be sufficient, especially in case of calcifications or/and <10 cysts.

References

Delavaud C, d’Assignies G, Cros J, et al. CT and MR imaging of multilocular acinar cell cystadenoma: comparison with branch duct intraductal papillary mucinous neoplasia (IPMNs). Eur Radiol 2014; 24: 2128–2136

Disclosure

No conflict of interest to be disclosed

Introduction

Crohn's disease (CD) is a chronic inflammatory bowel disease that is characterized by periods of active inflammation followed by periods of remission. Current Methods for defining Crohn's disease activity are limited by various factors including low specificity, bias, invasiveness, high costs, radiation exposure and patient preference. Therefore, an easy, noninvasive, inexpensive, user-friendly, and repeatable method for the assessment of disease activity is warranted. Abnormal body temperature is a natural indicator of illness. Infrared thermography (IRT) can map body surface temperature remotely. With the advent of modern infrared cameras, data acquisition, and processing techniques, it is now possible to have real-time high-resolution thermographic images. Inflamed bowel loops are hyper-vascular and hyperemic, as detected by high doppler signs of intestinal ultrasound and bowel wall contrast enhancement in MRE, and therefore can be detected using IRT.

Aims & Methods

Our aim was to examine thermal imaging using IRT as a noninvasive tool for detecting bowel wall inflammation and disease activity in Crohn's disease patients.
The design of the study was prospective non -interventional. Consecutive adult CD patients referred for an intestinal ultrasound (IUS) exam were included, and adult healthy volunteers were recruited from the general population. Thermal images were captured using a FLIR ONE thermal camera device (FLIR Systems, Inc. Wilsonville, OR, USA) that connects directly to smartphones and utilizes a frame rate frequency of 8.7 Hz, an object temperature range of -20°C to 120°C and thermal sensitivity of 100 mK . Disease activity was defined using IUS. Thermal images of the study population were processed and compared to the results of IUS in all participants. Our novel thermal image processing algorithms extracted texture and shape features of temperature distribution across the skin covering the region of interest (ROI).

Results

The study cohort included 147 CD patients and 14 healthy volunteers. Using IUS, disease activity was found in 100 CD patients (68%). All 14 healthy volunteers had a normal IUS. The average abdominal temperature measured in the Crohn's patients (both active and inactive) was significantly higher than that of the healthy volunteers (30.4⁰±2.9⁰ C vs. 28⁰±2.9⁰ C, p=0.0032). The average abdominal temperature measured in the Crohn's group with the active disease was also found to be significantly higher than that of the healthy volunteers (30.4±2.99 C vs. 28⁰±2.9⁰ C, p=0.0035). To differentiate between active CD and CD in remission, a new parameter was defined and extracted: the fractal dimension of gradient magnitude (FDGM). The mean FDGM was significantly higher in patients with active disease than in patients with normal IUS (1.66 vs 1.63, p=0.045).

Conclusion

We describe a novel easy-to-use tool for monitoring disease activity in CD. This new method can potentially be used by patients at home as well as an office-based exam that allows precise disease follow-up and disease activity monitoring.

Disclosure

Dan Carter: Consulting fees from Takeda, Abbvie, Taro, and Lapidot; speaker fees and/or research support from Takeda, Abbvie, Janssen, and Lapidot.