Clinical Case Summary

Introduction: We present the case of a 30-year-old patient with severe Crohn's disease (Montreal classification A2, L3, B3). The patient had been on infliximab therapy since March 2022 with partial clinical benefit and residual endoscopic and histologic disease activity (SES-CD 6, January 2023).
Case report: In October 2023 on physical examination, the patient showed the appearance of an erythematous and painful nodule at the level of the middle third of the posterior surface of the leg. After one week, the lesion appeared ulcerated, with a necrotic base and a violaceous, raised peripheral rim.(figure 1) After dermatologic evaluation, the diagnosis of pyoderma gangrenosum was posed. This was the pustular subtype, the variant of pyoderma most related to inflammatory bowel disease. The patient started corticosteroid therapy by oral somministration and IFX therapy was discontinued. At follow-up after twenty days from the start of therapy, the patient showed a slight reduction of the lesion in question, however, in the days to follow a similar lesion appeared at the level of the left gluteal region.(figure 2) Therefore, in consultation with the dermatology specialist, it was planned to tapering corticosteroid therapy until it was completely discontinued and to start the patient on off-label treatment with Upadacitinib at dosage of 45 mg in daily single administration for twelve weeks. At week 12, both lesions showed a marked improvement.(figure 3) In addition, the patient reported clinical benefit about bowel activity. Therefore, it was decided to continue Upadacitinib with a dosage of 30 mg 1 cp/day. At week 20 of therapy, lesion resolution and healing were noted.(figure 4)
Conclusions: Our cases support the efficacy of Upadacitinib for the treatment of complicated Crohn's disease with the presence of extraintestinal manifestations. and up to our knowledge this is the first report of a successful treatment with Upadacitinib in a patient with concomitant PG and CD.

References

Figure 1: lesion ulcerated,at the level of the middle third of the posterior surface of the leg , with a necrotic base and a violaceous, raised peripheral rim.
Figure 2: lesion at the level of the left gluteal region.
Figure 3: At week 12, both lesions showed important degree of improvement
Figure 4: lesion resolution

Clinical Case Summary

Introduction: Locally advanced pancreatic tumors can lead to both biliary and duodenal obstruction by invasion or compression. Quality of life is severely affected if obstruction occurs: jaundice, emesis and pain can become invalidating and patients become too frail for palliative chemotherapy and are sometimes declared unfit even for derivative surgery. Recently, endoscopic techniques under EUS or ERCP guidance are being used to create biliodigestive and enteral anastomoses.
Clinical case: A 75-year-old female was diagnosed with locally advanced pancreatic head adenocarcinoma in January 2024. The tumor was declared unresectable and chemotherapy was initiated. A plastic stent was inserted into the main biliary duct (MBD) to ensure biliary drainage. In May 2024, she presented with cholangitis and emesis. EGD revealed duodenal stenosis and ERCP failed due to tumor infiltration. A combined endoscopic approach was performed: EUS-guided hepatico-gastrostomy (EHG) for biliary drainage and EUS-guided gastro-enterostomy using a lumen-apposing metal stent (LAMS). In July 2024, the plastic stent was removed, and in August 2024, two fully covered 60 x 10 mm SEMS were inserted antegrade through the EHG into the MBD to improve patency. At 11 months post-intervention, the patient returned for routine reassessment, declaring good clinical performance: she remained asymptomatic, with routine blood tests, including bilirubin levels within normal range and with all stents patent and correctly positioned (confirmed radiologically and endoscopically). The patient was able to maintain oral intake and continue chemotherapy. No late adverse events were noted.
Conclusion: This case demonstrates the long-term clinical and technical success of a staged endoscopic triple bypass for the management of complex biliary and duodenal obstruction due to unresectable pancreatic cancer. The approach was minimally invasive, well tolerated and remarkably improved the patient's quality of life.

References

1. Adler, Douglas G MD; Baron, Todd H MD, FACP. Endoscopic Palliation of Malignant Gastric Outlet Obstruction Using Self-Expanding Metal Stents: Experience in 36 Patients. American Journal of Gastroenterology 97(1):p 72-78, January 2002. | DOI: 10.1111/j.1572-0241.2002.05423.x
2. Giovannini, Marc. (2019). EUS-guided hepaticogastrostomy. Endoscopic Ultrasound. 8. 35. 10.4103/eus.eus_47_19.
3. Dumonceau, Jean-Marc & Tringali, Andrea & Blero, Daniel & Devière, J & Laugiers, R & Heresbach, D & Costamagna, Guido. (2012). Biliary stenting: Indications, choice of stents and results: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline. Endoscopy. 44. 277-98. 10.1055/s-0031-1291633.
4. Van Der Merwe, S. W., Van Wanrooij, R. L., Bronswijk, M., Everett, S., Lakhtakia, S., Rimbas, M., ... & Van Hooft, J. E. (2022). Therapeutic endoscopic ultrasound: European society of gastrointestinal endoscopy (ESGE) guideline. Endoscopy, 54(02), 185-205. 10.1055/a-1717-1391

Introduction

Although the recommended method of an initial examination of hematochezia is colonoscopy, computed-enhanced CT (CECT) is an appealing diagnostic modality for the same disorder, because it has a superior ability of detecting active bleeding and it is widely available, fast, and minimally invasive. In many centers, CECT has already become an established method for characterizing the location of hematochezia. However, its impact on clinical courses of patients with colon diverticular bleeding is fully known. We conducted this study to assess them on the basis of single-center experience in Japan.

Aims & Methods

Consecutive 370 patients with colon diverticular bleeding from April 2002 to January 2023 were enrolled. Diagnosis of colon diverticular bleeding was based on total colonoscopy. Patients were divided into two groups who underwent initial examinations via CECT and colonoscopy. 
Patient attributes, clinical data, and outcomes (length of hospital stay, re-bleeding rate, blood transfusion units and 30 days survival rate) were retrospectively analyzed. The patient characteristics and outcomes were compared between two groups using χ2 test or Fisher’s exact test.

Results

279 patients were men (75.4%). The average age was 70.0(30-94) years old.  Initial CECT was performed to 204 patients (Group A) (54.9%) and remaining 166(group B).  
Patients in group A were more likely to have cerebrovascular disorder.
Findings for other characteristics were similar between two groups. 
In Group A, CECT revealed extravasation in 110 patients (53.9%). 
Emergent colonoscopy was performed in 118 patients (extravasation positive 100: negative 18) and found bleeding point in 46 patients (extravasation positive 43: negative 3). 
In Group B, emergent colonoscopy was performed in 70 patients and found bleeding point in 19(27.1%) patients. 
Patients in group A required more blood transfusion units than group B significantly (3.36 ± 6.28 units in group A vs. 1.53 ± 2.96 units in Group B, p=0.001).
No significant difference was observed in terms of length of hospital stay (10.64 ± 7.11 days in group A vs.9.95 ± 5.37 days in Group B ,p=0.32) , recurrent bleeding rate (23.6 % in group A vs. 23.4 % in Group B, OR 1.016 ,p=1) , and 30 days survival rate (99.5% in Group A vs. 100 % in Group B, OR 1.005 ,p=1)

Conclusion

Emergent colonoscopy, subsequent to initial CECT which revealed extravasation, can detect bleeding point more efficiently in patients with colon diverticular bleeding. But, CECT did not improve clinical outcomes of these patients in this study.

Introduction

Diverticular disease of the colon is one of the most common diseases in Western world. Despite in the natural history in most of cases diverticulosis remains asymptomatic or manifests with mild abdominal pain, complications may occur. Bleeding from diverticula is one of the most common complications and, despite it is usually a self-limiting event, it may lead to anemia or shock. Among the endoscopic interventions for active bleeding, direct or indirect clipping of the diverticulum is the most diffuse one. However, it has been hypothesized that endoscopic band ligation (EBL) may be more effective, since it may improve the chance to close the bleeding vessel, with a better outcome on long term. Therefore we performed a meta-analysis comparing clipping versus EBL for diverticular bleeding.

Aims & Methods

Literature search on main databases (PubMed, Web of science, SCOPUS, EMBASE) was performed in November 2022. Studies comparing clip versus EBL for acute diverticular bleeding were selected. We excluded case series, abstract and articles not written in English. The following outcomes were analysed: short term effectiveness, early rebleeding, tardive rebleeding and need for surgery or radiologic embolization. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculate according to Mantel-Haenszel method. Heterogeneity was estimated by I² statistic with chi square test, and, if present, a random effect model was used, otherwise a fixed one was adopted.

Results

Seven studies were selected, overall enrolling 2322 patients (979 in EBL and 1343 in clip groups). Immediate haemostasis was achieved in the EBL and clipping group respectively in the 96.8% and 96.5% (OR=0.94, 95% CI 0.59-4.19, p=0.79). Early rebleeding was observed more frequently in the clipping (25.0%) than in the EBL group (11.8%), with an OR=0.40 (95% CI 0.32-0.51, p<0.001). Similarly, tardive rebleeding was more common in the clipping arm (37.4%) than in the EBL (24.5%), OR=0.39, 95% CI 0.22-0.68, p=0.0001. Patients receiving clipping needed more frequently salvage surgery or embolization than EBL (1.48% versus 0.53%, OR=0.40, 95% CI 0.17-0.93, p=0.03).

Conclusion

Despite EBL and clip have similar effectiveness in achieving immediate haemostasis, EBL showed better effectiveness in maintaining it on longer interval times, with less probable need for major surgical/radiologic interventions.

Introduction

Endoscopic ultrasound-guided fine needles biopsy (EUS-FNB) is nowadays considered mandatory for the assessment of solid pancreatic lesions (SPLs) in the neoadjuvant era. Even if most recent guidelines suggest that not less than 3 passes are sufficient to obtain adequate histological characterization, the right number of needle passes with the newest generation of FNB needles remains a topic of debate. In our study we aim to evaluate if less than 3 passes are enough to ensure high rates of confirmed histological diagnosis with the newest generation of FNB cutting needles.

Aims & Methods

Consecutive patients with SPLs requiring tissue sampling through EUS-FNB were enrolled in our study between October 2022 and March 2023. Tissue sampling was performed by the same expert endoscopist through a new 22G needle with asymmetric three-prong tip with the slow-pull technique and fanning when possible. The number of needle passes was determined by the macroscopic onsite evaluation (MOSE), and samples, coming from different passes, were divided into different test tubes. Our endpoints were diagnostic accuracy, positive core procurement yield and sample quality considering each test tube separetely.

Results

53 lesions (of which 75% pancreatic ductal adenocarcinoma) were sampled with an average size of 31 mm (SD=12mm). Sampling was performed with 2 or 3 passes, according to MOSE. Regarding the first needle pass, diagnostic accuracy was 97% (51 confirmed histological diagnosis) which reached 98% considering the second needle pass. Sample adequacy reached approximately 99%. Positive core procurement and tissue quality were >95% in all test tubes. No major adverse events were detected.

Conclusion

In patients with SPLs, the newest generation of histology needles for EUS-FNB could ensure a high diagnostic accuracy with only one needle pass, becoming extremely relevant in terms of time-saving, cost-effectiveness and safety, especially in high volume centers. Due to the limited number of patients additional data are needed.

Introduction

Inflammatory cells and cytokines play an instrumental role in the pathogenesis and disease course of ulcerative colitis (UC) and are thus accepted therapeutic targets. NX-13 is a first-in-class, orally active, once-daily, gut-selective NLRX1 agonist in development for UC. NLRX1 is a mitochondrial associated protein with a novel, bimodal, immunometabolic mechanism which upregulates mitochondrial metabolism, reduces oxidative stress, and decreases pro-inflammatory cell differentiation and cytokine release broadly in mouse models of IBD¹. NX-13 was well tolerated and showed gut selectivity with low systemic drug exposure in Phase 1 studies reported previously^2,3. We now present data from the phase 1b study describing changes in tissue cytokine levels and related to clinical response.

Aims & Methods

In this double-blind phase 1B trial (NCT04862741)³, 36 patients with active UC (Total Mayo Score 4-10; Mayo endoscopic subscore 2-3) were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Delayed Release (DR) or Placebo QD for 4 weeks. Protein levels of IFNγ, IL-10, IL-12(p40), IL-17, IL-4, IL-6, IL-8, MCP1, and TNFα in colonic tissue from NX-13 treated patients collected at screening (baseline) and week 4 of treatment were determined by Human Cytokine/Chemokine Panel – Immunology Multiplex Assay (Millipore Sigma) normalized to total protein concentrations. Patients from all NX-13 dose groups with paired baseline and week 4 samples (n=18) were included in this analysis. Mann-Whitney U testing was used for comparisons between responders (Resp) and non-responders (NR).

Results

Baseline cytokines levels were not different between Resp (change from baseline of at least –3, or –30% in total Mayo Score) and NR. NX-13 treatment resulted in a decrease of multiple proinflammatory cytokines at week 4 compared to baseline in most patients, and especially in Resp. compared to NR at week 4 (Table 1). Primarily, the reduction (% change from baseline) of Th1 cytokines IL-12(p40) and IFNγ was greater in NX-13 treated patients with clinical response compared to NR, resulting in significantly lower values in Resp compared to NR at the end of the 4-week study. Similarly, IL-6 also tended to be lower among Resp. after 4 weeks of treatment with NX-13. Additionally, Th2 cytokine IL-4 values were significantly lower after 4 weeks of NX-13 in patients in clinical response compared to NR. Myeloid cell recruitment may also have been affected by cytokine changes induced by NX-13 as IL-8 and MCP levels were lower in clinical Resp. Reduced myeloid cell recruitment is consistent with higher levels of histologic remission in NX-13 treated patients³.

Conclusion

Broad changes in tissue cytokine expression were specifically observed in patients that responded to NX-13- after 4 weeks of treatment, compared to non-responders. These changes mirror those seen in preclinical mouse colitis models where a broad array of cytokines is reduced¹. The early onset of cytokine shifts associated with clinical response to NX-13 at week 4 is notable and will be assessed in the ongoing phase 2 NEXUS study in patients with moderate to severe UC (NCT05785715).

References

¹Leber, et al. J Immunol 203(12); ²Leber, et al. UEGW J 9(Supp); ³Verstockt, et al. JCC epub 11NOV2023

Disclosure

BS has received grant support from Pfizer (to institution); served as a consultant (served as a representative of Charité) for AbbVie, Arena, BMS, Boehringer, Celgene, Endpoint Health, Falk, Galapagos, Janssen, Landos, Lilly, Pfizer, PredictImmune, and Takeda; and has received speaker’s fees (served as a representative of Charité) from AbbVie, CED Service GmbH, Falk, Ferring, Galapagos, Janssen, Lilly, Pfizer, and Takeda; support for attending meetings/travel from Falk; and served as president of ECCO. | SV has received grants from AbbVie, J&J, Pfizer, Takeda, and Galapagos; consulting and/or speaking fees from AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, and Zealand Pharma. | AY reports consulting fees from Takeda, Prometheus Labs, Arena Pharmaceuticals, and Bristol Myers Squibb; and speaker bureau fees from Bristol Myers Squibb. | SS has received personal fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Dr Falk Pharma, Ferring, Fresenius, Galapagos, Genentech, GSK, Gilead, I-MAB Biopharma, Janssen, Lilly, Merck, Novartis-Sandoz, Pfizer, Protagonist, Takeda, and Theravance. | SD reports 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, TiGenix, UCB Inc., and Vifor; he reports lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, and Takeda. | RM is an employee of Landos. | FC is an employee of Landos. | BV has received grants from Abbvie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares, and Takeda; Speaker’s fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris. Consultancy fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepoint, Landos, Mylan, Inotrem, Ipsos, Janssen, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma and Viatris. | MCD reports consulting fees from AbbVie, Arena, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Gilead, Janssen, Pfizer, Prometheus Labs, and Takeda; and is founder and a shareholder of Trellus Health.

Introduction

Colonic diverticular bleeding (CDB) is the most common cause of acute lower gastrointestinal bleeding (ALGIB) and often requires blood transfusion. There are several studies regarding the use of restrictive blood transfusion for acute upper gastrointestinal bleeding, but there is only one previous study regarding the use of restrictive blood transfusion for ALGIB [1]. Therefore, the efficacy of restrictive blood transfusion for CDB remains unclear.

Aims & Methods

This study sought to elucidate the association between the restrictive blood transfusion strategy and the clinical outcomes in patients with CDB. We retrospectively analyzed 475 patients who were urgently hospitalized for CBD and received blood transfusions at two facilities between November 2013 and December 2021. Transfusion strategy was defined as the restrictive group when patients received transfusion for hemoglobin (Hb) ≤ 7 g/dl, and the liberal group when patients received for Hb > 7 g/dl. The hemoglobin cut-off value for restrictive blood transfusion was determined based on a prior randomized clinical trial regarding UGIB [2]. Rebleeding within 30-days, mortality within 30-days, and composite outcome within 30-days were evaluated. The composite outcome comprised the following endpoints: rebleeding, need for surgery or IVR for hemostasis, and mortality within 30 days. We also investigated medical costs during hospitalization. Logistic regression analysis was performed to calculate the odds ratios (OR) with 95% confidence interval (CI) to analyze associations between restrictive transfusion strategy and outcomes.

Results

Of 475 patients, 184 (38.7%) (124 males, 60 females, mean age 76.5±11.5 years) patients received blood transfusion. The mean hemoglobin levels at the time of transfusion in the restrictive and liberal groups were 6.3±0.6 g/dl and 8.2±1.2 g/dl, In the restrictive and liberal group, rebleeding within 30-days was 53.9% and 45.3% (P = 0.24), the mortality within 30-days was 1.1% and 0% (P = 0.30), the composite outcome within 30-days was 56.1% and 52.6% (P = 0.63), respectively. After adjusting for potential confounders, multivariate analysis revealed that restrictive transfusion strategy not associated with decreased rebleeding risk within 30-days, (P = 0.42 ; odds ratio [OR], 1.3), whereas endoscopic hemostasis significantly associated with decreased rebleeding risk (P < 0.01 ; OR 0.2). There was no statistically significant difference in total medical costs between the two groups (P = 0.68).

Conclusion

There were no statistically significant differences in rebleeding within 30-days, mortality within 30-days, and compositeoutcome within 30-days between the restrictive and liberal blood transfusion strategies. Restrictive blood transfusion may be a reasonable therapeutic strategy for patients with CDB, except for patients in which shock status cannot be withdrawn. However, further evidence is needed to advocated the efficacy of restrictive transfusion strategies for lower gastrointestinal bleeding.

References

[1] Kherad O, Restellini S, Martel M, Sey M, Murphy MF, Oakland K, et al. Outcomes following restrictive or free red blood cell transfusion in patients with lower gastrointestinal bleeding. Aliment Pharmacol Ther. 2019 Apr;49(7):919–25.
[2] Villanueva C, Colomo A, Bosch A, Concepción M, Hernandez-Gea V, Aracil C, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013 Jan;368(1):11–21.