Clinical Case Summary

A 27-year-old woman is admitted to a tertiary hospital for a sudden painful wound on the inner side of her upper arm. The patient stated that she had been diagnosed with ulcerative colitis 6 years ago and had been treated with prednisone and mesalazine, but was currently in remission and discontinued treatment. She was treated twice in the surgical ward for similar ulcers 2-3 years ago. Physical examination revealed a redness of ~10x6 cm in the lower third of the left upper arm and a necrotic area of 3 cm in the middle of the upper arm which was very painful to palpate. The patient was hospitalized for suspected extraintestinal signs of ulcerative colitis, but colonoscopy revealed no changes. The wound was treated with incision, lavage, necrectomy and a/b therapy according to the culture results. During the course of treatment, the patient developed a new skin lesion on the right hip and an unexpected decrease in prothrombin from 70% to 6%, which normalized after vitamin K injections. A wound biopsy revealed necrotic-inflammatory lesions, differentiating between autoimmune vasculitis and possible chemical damage. Suspecting a factitious disorder (Munchausen syndrome) the patient's rucksack was searched and syringes together with a small vial of liquid (subsequently identified as formalin) were found. Furthermore, it was revealed that patient's son was treated for 10 months in the other hospital due to deep necrotic wounds that are difficult to heal, immunodeficiency of unknown origin, repeated disruptions in the coagulation system (prothrombin 3%) and dead at age 11 month from secondary sepsis 2 years ago.
The hospital appealed to the prosecutor's office, a forensic psychiatric expert found the patient guilty, and the court sentenced her to 16 years' imprisonment for killing her son.

Clinical Case Summary

Background: Chronic intestinal pseudo-obstruction (CIPO) is a rare syndrome in which the symptomatology of intestinal obstruction occurs without any mechanical cause. This syndrome may reveal or complicate celiac disease during follow-up.
Cases presentation: We report two cases of 40 and 24-year-old women. The first is followed since the age of 8 for celiac disease on a poorly followed gluten-free diet and consulted for repeated pseudo-occlusive syndromes. the second was admitted to the surgery department for a recurrent occlusive syndrome which resolves after gastric aspiration, then referred to our service for exploration of chronic diarrhea. For both, no mechanical obstruction was found. Ionic disorders and lymphoma were also ruled out. The diagnostic of CIPO was retained. The intestinal mucosal biopsy was characteristic of celiac disease. The evolution was favorable under a gluten-free diet. Symptoms of CIPO never recurred.
Conclusion: Our observations highlight that CIPO may be a rare and severe complication of celiac disease, which should always be suspected since the gluten-free diet can improve symptoms and prevent recurrences.

Introduction

Total retocolectomy with ileal pouch anal anastomosis (IPAA) is the surgical procedure of choice for patients with ulcerative colitis (UC) refractory to clinical treatment and familial adenomatous polyposis (FAP) with many polyps in the rectum. Primary ileitis of the ileal pouch (IP) is one of the most common complications in UC, being rare in FAP. Previous studies have identified an increase in pro-inflammatory cytokines, as well as alterations in the apoptosis and macroautophagy pathways markers in the IP mucosa of UC patients, compared to those with FAP and normal distal ileum (controls). Since autophagy and apoptosis can be modulated by endoplasmic reticulum (ER) stress, we investigated this pathway in IP of UC compared to PAF and controls.

Aims & Methods

The aim was to evaluate the modulation of ER stress in the IP mucosa of UC and FAP patients who underwent IPAA, compared to controls. Thirty-two patients were included, ten in the UC group, twelve in FAP group and ten in the control group. Patients who had undergone ileostomy closure for less than one year and had clinical, histological, or endoscopic evidence of pouchitis were excluded. The patients underwent routine colonoscopy, and biopsies were performed from the IP. For the control group, biopsies were taken from the normal distal ileum. The local Ethics Committee approved the study. The biopsies were processed for RNA extraction and subsequent gene expression analysis using the quantitative PCR (qPCR) technique. The following transcripts were investigated: IRE1 (ERN), PERK (EIF2AK3), ATF6, GRP78 (HSPA5), GRP94 (HSP90B1), ATF3, STC2, DDIT3, DNAJC3, and CALR. Nonparametric tests were used for statistical analysis, with a significance level of p<0.05.

Results

The pouchitis disease activity index (PDAI) was applied to verify the absence of pouchitis, with all patients scoring lower than 7. There was no increase in the transcriptional level of the main ER stress pathway markers (ERE1, PERK, and ATF6) in the IP without pouchitis. However, there was a significantly lower expression of DDIT3 in the UC and FAP groups compared to the control (p≤0.05), which may suggest a deficiency in counterbalance the ER stress activation. On the other hand, concerning the UPR pathway markers, the levels of CALR and HSP90B1 were significantly higher in the IP of UC compared to the respective IP afferent loop (p≤0.05), supporting potential activation of the ER stress in the IP in the UC group. Additionally, the transcriptional level of ATF3 was significantly higher in the PAF group compared to the control (p≤0.05), which may indicate a counter-regulatory mechanism in response to tissue damage, which was not verified in the UC group.

Conclusion

Our findings demonstrated that markers of the unfolded protein response (UPR) signaling pathway, which is activated in response to ER stress, are modulated in the IP mucosa of UC patients, even in the absence of pouchitis. These results may explain the propensity to IP inflammation in UC patients. They may guide the identification of additional molecular pathways contributing to inflammation of the IP and the search for new therapeutic targets.

References

1. Negreiros LMV, Pascoal LB, Genaro LM, et al. Pouchitis: insight into the pathogenesis and clinical aspects. Am J Transl Res. 2022 Jul 15;14(7):4406-4425.
2. Rodrigues BL, Dotti I, Pascoal LB, et al. Endoplasmic Reticulum Stress in Colonic Mucosa of Ulcerative Colitis Patients Is Mediated by PERK and IRE1 Pathway Activation. Mediators Inflamm. 2022 Feb 9;2022:6049500.
3. Paiva NM, Pascoal LB, Negreiros LMV, et al. Ileal pouch of ulcerative colitis and familial adenomatous polyposis patients exhibit modulation of autophagy markers. Sci Rep. 2018 Feb 8;8(1):2619.
4. Qiao D, Zhang Z, Zhang Y, Chen Q, Chen Y, Tang Y, et al. Regulation of Endoplasmic Reticulum Stress-Autophagy: A Potential Therapeutic Target for Ulcerative Colitis. Front Pharmacol. 2021;Volume 12-2021.

Clinical Case Summary

Inflammatory Bowel Disease (IBD) can be a chronic, disabling condition. Long-term symptoms, failed therapies, repeated hospital admissions and impairment of social functioning can result in significant emotional trauma (Taft et al., 2022). Such patients are at an increased risk of mood disorders and abnormal eating behaviours. Severely affected patients can be managed using a trauma informed approach (Bugwadia et al., 2024).
A 50-year-old woman with a BMI of 14.9 kg/m2, history of ileocolic resection for Crohn’s Disease (CD), anxiety, depression, anorexia nervosa and irritable bowel syndrome presented with symptoms of abdominal pain, diarrhoea and weight loss despite advanced medical therapy. A stricture at the site of her ileocolic anastomosis was identified, with chronic distention of the upstream ileum. Surgical resection with stoma formation was recommended by the multidisciplinary team.
Due to the number and complexity of her co-morbidities, a tailored, trauma-informed approach was used to facilitate her care. Pre-operatively, counselling was performed in a compassionate, staged manner in multidisciplinary consultations. Input from clinical psychology, nutrition and stoma care helped to de-escalate catastrophic thoughts, building trust. Encouragement to engage with peer-support groups improved her confidence. Post-operative care was responsive to her needs with further support from clinical psychology and nutrition. Early closure of the ileostomy allowed return to normal function as soon as was possible.
A trauma-informed care approach combining a team of IBD clinicians, dieticians, stoma nurses and clinical psychologists was crucial in managing a complex case of co-morbid anxiety, depression, anorexia and CD.

References

Bugwadia, A. K., Reed, S., Shapiro, M., Dave, S., Jayswal, N., Kohler, D. & Keefer, L. (2024) Medical trauma in young adults with inflammatory bowel disease: The role of trauma-informed care. Health Care Transitions. 2 100044. 10.1016/j.hctj.2024.100044.
Taft, T. H., Quinton, S., Jedel, S., Simons, M., Mutlu, E. A. & Hanauer, S. B. (2022) Posttraumatic Stress in Patients With Inflammatory Bowel Disease: Prevalence and Relationships to Patient-Reported Outcomes. Inflammatory Bowel Diseases. 28 (5), 710–719. 10.1093/ibd/izab152.

Introduction

Upadacitinib (UPA) is an oral selective small molecule JAK inhibitor emerged as a promising therapeutic agent for immune-mediated inflammatory diseases. Recently, UPA has been evaluated for the treatment of moderate-to-severe ulcerative colitis (UC) with encouraging phase III trials. The aim of this real-life observational study is to explore the effectiveness and safety of UPA in UC patients in a large multicenter italian cohort.

Aims & Methods

UPAREAL-UC is an observational multicenter study involving 36 IBD centers in Italy. UC patients who have been prescribed UPA between 01.2023 and 11.2024 were enrolled and prospectively followed-up. Main outcomes were steroid-free clinical remission, biochemical remission and treatment persistence. Five main evaluation time-points were defined: T0 (baseline), T1 (8weeks), T2 (16weeks), T3 (26weeks) and T4 (52weeks). At each time-point, partial Mayo score (pMS), fecal calprotectin (FC) and C-reactive protein (CRP) levels were recorded. Steroid-free clinical remission was defined as pMS<2, FC remission as FC <250 ug/gr, CRP remission as CRP<0,5 mg/dl. Treatment-related adverse events were also reported. To investigate the correlation between the variables Fisher exact test was used.

Results

Among 367 UPA patients included in the multicenter on-going study, we present the results of the first 250 patients with at least 12 months of follow up (enrolled until 03.2024). At baseline all patients were bio-exposed, the majority of them presented with moderate-severe UC and the median age was 40 years. Extraintestinal manifestations were observed in 10 % of patients and cardiovascular risk factors in about 15%.
Steroid-free clinical remission was achieved in 175 (70%), 197 (78,8%), 195 (78%) and 175 (70%) patients at T1, T2, T3 and T4, respectively. CRP and FC showed a significative reduction with a biochemical remission at T3 and T4 in about 70% of patients for both CRP and FC. The composite endpoint, defined as the presence of steroid-free clinical remission and biochemical remission (both CRP and FC), was achieved in 135 patients (54%) at T3 and in 145 patients (58%) at T4. All these improvements were statistically significant (p<0,0001). Treatment persistence at 12 months was 82 %. The need for a prolonged induction occurred in 54% patients. Adverse events occurred in 12,8 % patients, treatment failure occurred in 16% with a median time to failure of 18 weeks.

Conclusion

These preliminary data coming from large on-going multicentric IG-IBD study conducted in a real-life setting, confirm promising effects of UPA in inducing steroid-free clinical remission and in normalizing markers of inflammation. A significant 12-months treatment persistence was observed. No serious adverse events occurred. Long-term prospective data, including endoscopic and histologic evaluations, are needed and will be available at the end of this ongoing study.

Introduction

Primary thromboprophylaxis is used in the post-partum and the post-surgical period. 2014 Canadian Association of Gastroenterology guidelines and a 2021 Nature Reviews consensus recommend outpatient thromboprophylaxis only for those ambulatory inflammatory bowel disease (IBD) patients at high risk of thromboembolic events.

Aims & Methods

We aimed to analyse our inpatient burden and our rate of post-discharge thromboembolic (TEEs) in those with primary and secondary diagnoses pertaining to IBD. We also aimed to identify associated risk factors.
Our hospital inpatient and radiology databases were queried for discharges with primary and secondary diagnoses pertaining to IBD and scans pertaining to TEEs respectively.

Results

1,601 discharges pertaining to 954 individual patients were identified over the 13-years ended 2024. 54% (n=870) were female. Median age was 44 (IQR:32-59). 58% (n=932) pertained to Crohn’s disease.
Investigations for TEEs were performed during 117 admissions (7.3%). 10 patients had inpatient TEEs (0.6%). Age ≥ 50 years was significantly associated with inpatient TEE (Odds ratio [OR]: 1.89; 95% confidence intervals [CI]: 1.13-3.16; p=0.01). Male gender (OR: 0.92; 95% CI: 0.59-1.44; p=0.72), ulcerative colitis subtype (OR: 1.51; 95% CI: 0.95-2.41; p=0.08) and inpatient surgical intervention (OR: 1.39; 95% CIs: 0.89-2.17; p=0.15) were not significant associated factors.
63 discharges (3.9%) had imaging querying TEEs performed within 180 days. Six patients (0.4%) had TEEs within this time frame. No significant associations were identified for age ≥50 years (OR: 1.16; 95% CIs: 0.68-1.99; p=0.59), male gender (OR: 0.84; 95% CIs: 0.48-2.17; p=1.47, p=0.55), ulcerative colitis subtype (OR: 1.12; 95% CIs: 0.65-1.91; p=0.68), inpatient surgical intervention (OR: 1.37; 95% CIs: 0.79-2.35; p=0.26) or prior VTE (OR not calculable) in relation to post-discharge TEEs.

Conclusion

Our incidences of inpatient and post-discharge TEEs were low over 13-years. In agreement with international guidelines, we recommend against the need for routine primary prophylaxis in the post-discharge ambulatory period.

References

1. Nguyen GC, Bernstein CN, Bitton A, et al. Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology. Gastroenterology. 2014;146(3):835-848.e6. doi:10.1053/j.gastro.2014.01.042
2. Olivera PA, Zuily S, Kotze PG, et al. International consensus on the prevention of venous and arterial thrombotic events in patients with inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021;18(12):857-873. doi:10.1038/s41575-021-00492-8