Clinical Case Summary

There are limited available rescue therapy options for refractory acute severe ulcerative colitis (ASUC). Cyclosporine is used in steroid refractory and steroid resistant ASUC patients and based on our report, may also help steroid intolerant patients. Here, we describe the case of a 22-year-old male with left sided UC who presented with ASUC to our tertiary IBD center in Abu Dhabi in the United Arab Emirates. In clinic, our patient reported 20 watery bowel movements per day associated with nocturnal episodes mixed with blood, abdominal cramps.He had lost 12 kg over 6 months. He reported having failed escalating doses of infliximab and adalimumab in the past. Additionally, he had developed severe peripheral neuropathy on steroids and had to stop taking them. On examination, vital signs were normal with generalized abdominal tenderness. The patient was admitted to the hospital. Labs revealed severe anemia, low albumin, elevated CRP, ESR and fecal calprotectin. His abdominal X-ray was unremarkable. Stool for C diff and blood CMV DNA by PCR were negative. On flexible sigmoidoscopy, he had severe contiguous inflammation to a Mayo endoscopic score of 3. Subsequent biopsies confirmed severe active chronic colitis without CMV infection. On the day of admission, we induced him with vedolizumab 300 mg intravenous infusion, started intravenous cyclosporine and placed him concurrently on oral azathioprine. Over the next week, he had responded. By day 12, he was in clinical remission and discharge home. When followed in clinic 1 week post discharge, he remained in clinical remission on vedolizumab, oral cyclosporine and oral azathioprine. At week 6 post discharge, he was in clinical remission as well on the same regimen. In conclusion, this report is a good example of the possibility of using combination of cyclosporine, vedolizumab and azathioprine as concurrent induction therapy for patients with ASUC.

References

Gisbert JP, García MJ, Chaparro M. Rescue therapies for steroid-refractory acute severe ulcerative colitis: A review. Journal of Crohn's and Colitis. 2023 Jan 18
Dai C, Huang YH, Jiang M. Combination therapy in inflammatory bowel disease: Current evidence and perspectives. International Immunopharmacology. 2023 Jan 1;114:109545.
Pellet G, Stefanescu C, Carbonnel F, Peyrin-Biroulet L, Roblin X, Allimant C, Nachury M, Nancey S, Filippi J, Altwegg R, Brixi H. Efficacy and safety of induction therapy with calcineurin inhibitors in combination with vedolizumab in patients with refractory ulcerative colitis. Clinical Gastroenterology and Hepatology. 2019 Feb 1;17(3):494-501.

Introduction

Enteropathy Associated T Cell Lymphoma (EATL) is a rare and highly aggressive T-cell non-Hodgkin’s lymphoma (NHL)¹ that is strongly associated with refractory coeliac disease (RCD), particularly type 2 RCD ², and possibly inflammatory bowel disease (IBD). The incidence and prevalence of both coeliac disease³ and IBD⁴ have been rising around the world for several decades, including in both Englandand Denmark^​. Some of the potential drivers of EATL are the antigen-driven proliferation of intra-villous T-cells from coeliac disease and chronic inflammation in IBD, so it is important to understand if changes in these diseases are altering clinical presentations of EATL and its survival.

Aims & Methods

Our aim was to describe the contemporary incidence and survival of EATL from two European countries on a national scale, given the rising incidence and prevalence of coeliac disease and use of immunosuppression in inflammatory bowel disease, to give further insights into epidemiology of this rare and often fatal malignancy.
People with EATL were identified from national cancer registries from 2013-2019 in England and 2004-2020 in Denmark. Within each country we used direct standardisation to estimate incidence, Poisson regression to compare incidence between groups and Cox regression to assess overall survival.

Results

172 and 39 patients were identified in England (E) and Denmark (DK) respectively with a mean age at diagnosis of 66 and 68 years. Approximately half of all cases had coeliac disease (E 52%, DK 41%), and ~7% (E 6%, DK 8%) had inflammatory bowel disease (Table). The overall age-standardised incidence rate was (E) 0.48 (95% CI 0.41-0.56) and (DK) 0.44 (95% CI 0.30-0.58) per million population per year. In both countries incidence was higher in older age groups. The 5-year overall survival was 10% (95% CI: 6%-18%) in England and 20% (95% CI: 9%-33%) in Denmark. Those with coeliac disease fared better than those without: (adjusted Hazard Ratio E 0.65 (95% CI 0.45-0.93), DK 0.57 (95% CI 0.26-1.27)).

Table: Characteristics of people with EATL in England (2013-2019) and Denmark (2004-2020)

Conclusion

This analysis of two nationwide cancer registries is the largest population-based study to date to provide contemporary and comprehensive epidemiologic estimates of all ICD-O-3 coded EATL. It shows that a higher incidence is associated with older age, male sex (in England) and that half of cases also have coeliac disease. Our finding of the high proportion of people with inflammatory bowel disease compared to the background prevalence in both countries requires further investigation, as reasons for this are unclear, but it could be related to chronic inflammation or immunosuppression. Overall survival is poor and gets worse in older age groups but is better in those with coeliac disease, following surgical resection and those able to tolerate intensive therapies.

References

1. Ferreri AJ, Zinzani PL, Govi S, et al. Enteropathy-associated T-cell lymphoma. Crit Rev Oncol Hematol 2011;79:84-90.
2. Pelizzaro F, Marsilio I, Fassan M, et al. The Risk of Malignancies in Celiac Disease-A Literature Review. Cancers (Basel) 2021;13.
3. King JA, Jeong J, Underwood FE, et al. Incidence of Celiac Disease Is Increasing Over Time: A Systematic Review and Meta-analysis. Am J Gastroenterol 2020;115:507-525.
4. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2017;390:2769-2778.

Introduction

Several therapeutic options are now available for the treatment of moderate-to-severe ulcerative colitis (UC): pivotal trials have reported efficacy and safety of anti-TNF-α, Vedolizumab (VDZ), Ustekinumab (USTE) and Tofacitinib (TOFA) but comparative data are scanty and only one head to head trial (Varsity trial) is available. Network meta-analysis from Singh et al. demonstrated that TOFA and USTE are the best options in anti-TNF exposed patients. Real-worlds studies are discrepant most reporting similar efficacy of second-line drugs. Thus, the optimal sequence of therapeutic choices is still unclear.

Aims & Methods

Our aim was to analyze comparative efficacy of VDZ, TOFA and USTE in a homogeneous cohort of UC patients in a real life setting. We report data of a retrospective-prospective study conducted between 2020 and 2023 in our tertiary referral center. The primary outcome (PO) was clinical response (assessed by partial Mayo score). Secondary outcomes were: steroid-free remission (SFR), adverse events (AEs), time and reasons for treatment discontinuation, surgery and hospitalization rate. All outcomes were investigated at 8 weeks and at the end of follow-up (FU). At the end of FU another secondary outcome was therapy optimization. All data were analysed using the Medcalc program.

Results

73 patients (65,75% males, mean age 55 yrs) with moderate-to-severe UC were included, mostly (84%) anti-TNF experienced, treated with TOFA (27,4%), USTE (26%) or VDZ (46.6%). Average FU was 11 months. TOFA showed a significant higher clinical response rate at week 8 (80% vs 58,8% VDZ and 42,1% USTE; p = 0,016) while there were no significant differences at the end of FU. SFR rate didn’t reach the statistical significance at week 8 and at the end of FU (55% TOFA, 58,8% VDZ and 47,37% UST). 4 patients experienced AEs: 2 paresthesias and 1 mild AST/ALT elevation in the TOFA group; 1 fever of unknowkn origin (FUO) in the USTE group. Treatment discontinuation rate didn’t show significant differences. All discontinuations were for treatment failure except the patient with FUO. All the other AEs showed spontaneous resolution. None of the patients was submitted to surgery or hospitalized. Optimisation rate at the end of FU was higher in the VDZ group (50% vs 25% TOFA and 15,8% USTE ; p value (VDZ vs UST 0,009; VDZ vs TOFA 0,05).

Conclusion

TOFA was more effective at wk 8 in comparison with USTE in agreement with previous studies which have documented an increased speed of action of JaK-inhibitors. In the long run efficacy results are similar, thus not confirming superiority of TOFA and USTE as compared to VDZ observed in other studies and reported by national and European guidelines. Treatment optimization was more frequently required with VDZ. Further head-to-head trials and real-world studies are needed to investigate the comparative efficacy of second-line therapeutic agents after anti-TNF failure.

Disclosure

I

Clinical Case Summary

Male, 72 years old, past medical history of diabetes mellitus and diabetic gastroparesis with only partial improvement after medical treatment with prokinetics, antiemetics and oral antidiabetic drugs.
Due to gastric adenocarcinoma, he underwent curative submucosal dissection(ESD) 2 years before and developed pyloric stenosis 1 month after ESD, refractory to endoscopic dilation and not amenable to placement of a biodegradable stent due to stomach morphology.
The patient was admitted to the to the Emergency Department after 2 weeks of postprandial vomiting, weight loss(12%/1 month) and 2 days of disorientation. On examination, he was partially oriented, hemodynamically stable, with mucocutaneous dehydration.
He was hospitalized, started on prokinetics and a nasogastric tube was placed for drainage. Analysis results on admission were normal except for a cystitis and empirical antibiotic was initiated.
During hospitalization, he suffered acute depression of consciousness with stupor and bilateral ophthalmoplegia, followed by delirium.
CT angiography excluded acute vascular events and cerebrospinal fluid(CSF) cytochemical analysis was normal.
Due to clinical suspicion of Wernicke's encephalopathy, he was started on intravenous thiamine at therapeutic dose, anticonvulsant, antibiotic at meningeal dose and antiviral, while waiting for microbiological results.
MRI revealed hypersignal in T2 and FLAIR with restriction in the diffusion study in the midbrain and the thalamus - findings suggestive of Wernicke's Encephalopathy. The remaining study, including EEG and complete CSF analysis excluded other etiologies.
There was a progressive improvement of aphasia, apraxia, ataxia and nystagmus. After motor rehabilitation and vitamin supplementation, 6 months later, he maintains a short-term memory deficit (Korsakoff Syndrome).
Wernicke's Encephalopathy due to gastroparesis is a rare occurrence in the literature with potentially irreversible sequelae, as illustrated.

References

Introduction

Patients with immune mediated inflammatory diseases (IMIDs) on immunosuppressive therapies have attenuated vaccine responses (1-3) and are prone to severe infections. Knowledge of COVID-19 outcome following vaccine and hybrid immunity, and identification of protective anti-Spike antibody concentrations are important to further develop vaccine strategies in this vulnerable patient group.

Aims & Methods

In this prospective observational study, adult patients with IMID on immunosuppressive therapies were followed from February 15, 2021, to February 15, 2023. Throughout the study, patients and controls reported data regarding COVID-19, COVID-19 related hospital admissions were recorded from The Norwegian Patient Registry. Anti-Spike antibodies were assessed 2-4 weeks following vaccination and COVID-19. The objectives of this study were to investigate the outcomes of COVID-19 in a large cohort of IMID patients compared to healthy controls, and to identify any associations between anti-Spike antibody concentrations and disease course.

Results

Of 2250 IMID patients included in the study, a total of 1729 with a documented COVID-19 history were included in the present analyses (305 Crohn’s disease, 215 ulcerative colitis, 648 rheumatoid arthritis, 272 psoriatic arthritis, and 289 spondyloarthritis) (median age 54 years (IQR 42-64), 971 (56 %) females). Of the patients, 1080 of 1729 (62%) used anti-TNF treatment (65% monotherapy, 35% combination therapy).
1140 (66%) of patients and 236 of 350 (67%) healthy controls (HC) reported COVID-19, the majority (85%) within the Omicron era. COVID-19 reinfection was reported in in 141 (12%) patients and 32 (14%) HC (p=0.66). Compared to hybrid immunity (COVID-19 after three vaccine doses), the risk of COVID-19 was six times higher following vaccine series only (HR 5.9, (95% CI [4.45, 7.80]), p<0.001). Anti-Spike antibody concentrations <8000 BAU/ml were predictive of COVID-19 after three (HR 1.5 (95% CI [1.14, 1.90]), p=0.003) and four vaccine doses (HR 1.4 (95% CI [1.13, 1.83]), p=0.003), and in hybrid immunity (HR 2.6 (95% CI [1.32, 5.13]), p=0.006). In the entire cohort, the median anti-Spike antibody concentration after the 2^nd vaccine dose was 2823 BAU/ml (IQR 999-6199), after the 3^rd dose 6529 BAU/ml (IQR 2325-10140), after the 4^th dose 7624 BAU/ml (3809-12751) and following hybrid immunity 23506 BAU/ml (11423, 37007). Hospitalisation due to COVID-19 (severe disease) occurred in 22 (2%) patients, 9 (41%) before any vaccination, and none of HC. Four patients were admitted to intensive care. Prior to hospitalisation, the median anti-Spike antibody concentration was 444 BAU/ml (IQR 31-1634). Patients with severe disease were older than non-hospitalised (median age 61 years (IQR 48-74) vs. 54 (42-64), p=0.04) and had a higher frequency of comorbidities (19/22 (86%) vs. 474/1118 (42%), p=0.02). No COVID-19 related deaths occurred.
Prolonged COVID-19 (symptoms >14 days) were reported by 201 (18%) patients compared to 29 (12%) HC (p=0.09). The risk of prolonged disease was higher in the vaccine group compared to the hybrid group (HR 8.5 (95 % CI [3.84, 18.90]), p<0.001).

Conclusion

IMID patients and healthy controls had a comparable occurrence of COVID-19, prolonged disease and reinfection. However, severe disease developed only in the patient group. Hybrid immunity protects against COVID-19 and prolonged disease. A high anti-Spike antibody concentration protects against COVID-19, supporting the role of repeated vaccination in IMID patients on immune-suppressive therapy.

References

1. Jorgensen KK, Hoivik ML, Chopra A, Benth JS, Ricanek P, Moum PB, et al. Humoral immune response to SARS-CoV-2 vaccination in patients with inflammatory bowel disease on immunosuppressive medication: association to serum drug levels and disease type. Scand J Gastroenterol. 2023:1-9.
2. Bjorlykke KH, Orbo HS, Tveter AT, Jyssum I, Sexton J, Tran TT, et al. Four SARS-CoV-2 vaccine doses or hybrid immunity in patients on immunosuppressive therapies: a Norwegian cohort study. Lancet Rheumatol. 2023;5(1):e36-e46.
3. Syversen SW, Jyssum I, Tveter AT, Tran TT, Sexton J, Provan SA, et al. Immunogenicity and Safety of Standard and Third-Dose SARS-CoV-2 Vaccination in Patients Receiving Immunosuppressive Therapy. Arthritis Rheumatol. 2022;74(8):1321-32.

Disclosure

Have received speakers bureaus from Bristol-Myers Squibb and Roche

Introduction

Endoscopic suturing offers a novel minimally invasive technique for deploying full thickness sutures in the gastrointestinal (GI) tract. Indications range from defect closure, post operative leaks, fistula repair, stent fixation and tissue plication for endoscopic sleeve gastroplasty.
Here we report our updated experience of endoscopic suturing for non-bariatric applications in the upper GI tract using the Apollo OverStitch^TM device (Apollo Endosurgery, Austin, Texas). This represents the largest and most diverse case series in a UK cohort of patients.

Aims & Methods

We retrospectively evaluated cases where the Apollo OverStitch^TM device was used at our tertiary upper GI centre. The primary outcomes were immediate technical and clinical success. Technical success was defined as the successful application of sutures. Immediate clinical success was defined according to indication. For defect closure this was evaluated using on the table fluoroscopy/endoscopic visualisation. For stent fixation it was determined by the absence of stent migration at follow up endoscopy.
Secondary outcomes included defect recurrence at follow up investigation. We also evaluated long term clinical success by assessing for resolution of the index clinical issue at the time of latest follow up.

Results

The Apollo OverStitch ^TM device was used 56 times across 35 patients (57% female) between August 2018 and March 2023. The mean age of patients at the time of the index procedure was 58 (+/-17.3 years). Outcomes according to indication are highlighted below (Table 1).
There were five cases (5/56, 8.9%) of technical failure. Three (3/5, 60%) involved iatrogenic perforations at the junction between D1/D2. Three cases (3/37, 8.1%) of immediate clinical failure were reported for the defect closure cohort. In the defect closure cohort there was a recurrence rate of 61.8% (21/34), with a long term clinical success rate of 68.2% (15/22). 14 cases of stent fixation were conducted with a stent migration rate of 35.7% (5/14).
There were two (2/56, 3.6%) cases of bleeding following endoscopic suturing. In both cases bleeding was stemmed endoscopically on the table and prior to the end of the procedure.

Conclusion

Our case series suggests that the Apollo OverStitch^TM device can be used for a diverse range of indications with high rates of immediate technical and clinical success.
We note a high recurrence rate reflecting that many defects require repeat suturing attempts to achieve durable long term closure. We postulate that this may be related tissue epithelisation and/or friability impacting opposition. Furthermore, technical failure occurred most with perforations at the D1/D2 junction. This is likely related to acute angulation which impedes the ability to deploy sutures.
The heterogenous follow up data from this case series impacts the ability to draw firm conclusions regarding long term outcomes. There is an ongoing prospective multicentre registry which will assist in evaluating long term outcomes.