Introduction

Biological therapy in IBD patients is one of the cornerstones of treatment. For patients with loss of response while on maintenance therapy, options for dose escalation with the same agent are used to avoid switching targets, and this is done through a reinduction and dose intensification. While dose escalation is standard treatment with anti-TNF agents, current data on the efficacy of dose optimisation with ustekinumab in real life is limited.

Aims & Methods

The aim of the study is to assess the efficacy of dose optimisation (reinduction and intensification) therapy with Ustekinumab and to identify prognostic factors associated with clinical response. We performed a retrospective cohort study of patients that received dose optimisation with ustekinumab between January 2016 to July 2022. Demographic and clinical characteristics were obtained from the medical records. To assess for prognostic factors, responders and non-responders were compared using logistic regression analysis.

Results

A total of 94 patients were on ustekinumab treatment, and from these, 32 (30%) patients required dose optimisation during follow-up. The characteristics of patients included are summarized in Table 1. In 16 (50%) patients dose optimization was performed due to lack of response during the induction with Ustekinumab, the other 16 patients (50%) were intensified due to secondary failure. There were 15 (46.9%) patients in whom intravenous reinduction was performed prior to intensification. Three types of intensification were performed: 90mg subcutaneous every 4 weeks, 90mg subcutaneous every 6 weeks or 130mg intravenous every 4 weeks.
In 23 (72%) patients clinical remission was obtained after dose optimisation and were considered responders for logistic regression analysis. Extraintestinal manifestations (p=0.03) and secondary failure to Ustekinumab (p=0.049) were associated with a better response. No significant differences were observed between the type of intensification, the fact that they received prior reinduction or other demographic characteristics.

	n = 32
Gender (% women)	18 (56,2%)
Smokers (%)	8 (25%)
Disease type (%) Crohn’s disease Ulcerative colitis	27 (84,4%) 5 (15,6%)
Disease extension: Crohn’s disease (L1-L2-L3-L4) Ulcerative colitis (E2-E3) Behaviour in Crohn’s disease (B1-B2-B3)	L1 12(37,5%), L2 3 (9,4%), L3 9 (28,1%), L4 3 (9,4%) E2 1 (3,1%), E3 4 (12,5%) B1 9 (28,1%), B2 7 (21,9%), B3 9 (28,1%), B2+3 2 (6,3%)
Surgery (%) Perianal disease (%) Extraintestinal manifestations (%)	10 (31,3%) 14 (43,8%) 15 (46,9%)
Previous treatments (%) Naive Immunosupressor Biologic	4 (2,5%) 19 (59,4%) 28 (87,5%)
Only intensification Reinduction + intensification	17 (53,1%) 15 (46,9%)
Reason for reinduction + intensification Primary failure Secondary failure	16 (50%) 16 (50%)
Type intensification 90mg sc /4 weeks 90mg sc /6 weeks 130mg iv /4 weeks	17 (53,3%) 5 (15,6%) 10 (31,3%)

Table 1. Demographic data and prognostic factors of the cohort.

Conclusion

Dose optimization with ustekinumab is useful in clinical practice with a good response rate, specially in patients with secondary failure.

Clinical Case Summary

Whipple’s disease (WD), caused by Tropheryma whipplei, is a rare, multisystemic infection with a wide spectrum of clinical presentations. It may manifest acutely with nonspecific symptoms such as diarrhea, abdominal pain, fever, and fatigue, or present chronically. Diagnosis can be challenging due to its diverse manifestations, including cardiac, pulmonary, and neurological involvement. We describe a case of a 54-year-old male with a background of peroneal nerve dysfunction, admitted for progressive epigastric pain, nausea, vomiting, altered bowel habits, and recent mood changes. A comprehensive diagnostic evaluation was undertaken, including blood tests, abdominal ultrasound, computed tomography, and upper gastrointestinal endoscopy with biopsy. Diagnostic investigations revealed elevated cholestatic and pancreatic enzymes, raised CRP and ferritin levels, esophagitis, and distal duodenal swelling obstructing endoscope passage with inflammation around the ampulla of Vater. There were features of chronic pancreatitis with calcifications, pseudocysts (up to 27 mm), dilated Wirsung’s duct, and enlarged crescent lymph nodes. Histopathology showed extensive macrophage infiltration, and PAS staining was suggestive of T. whipplei infection. The patient was successfully treated with Ceftriaxone 2g orally daily for 30 days, followed by Trimethoprim/Sulfamethoxazole 960mg twice daily for one year. This case highlights an atypical presentation of WD, manifesting as upper gastrointestinal obstruction and recurrent acute pancreatitis, probably due to duodenal and ampullary inflammation impairing bile flow. It underscores the importance of considering WD in the differential diagnosis of complex and unexplained gastrointestinal symptoms. Presentations involving upper gastrointestinal obstruction and pancreatitis are rare. Early identification through intestinal biopsy and appropriate antimicrobial therapy is critical to avoid irreversible complications and improve outcomes.

References

Illustrative material:
1. Upper gastrointestinal endoscopy: view of the descending duodenum
2. Abdominal CT scan
3. Pathological findings: PAS staining

Clinical Case Summary

Pancreatic tuberculosis is rare, even in regions where the disease is highly prevalent. Its incidence is less than 4.7% (14/297 cases) in a large tuberculosis autopsy series by Auerbach et al. (1944). Symptoms are vague and non-specific, while radiologic features can mimic pancreatic carcinoma. Due to its nature of presenting as a pancreatic mass, unwarranted surgical interventions may diminish the patient’s quality of life. We presented a case of a 53-year-old male with a ten-week history of abdominal pain, febrile episodes, and weight loss. Ultrasound and magnetic resonance cholangiopancreatography (MRCP) revealed a pancreatic head and body mass causing moderate extrahepatic, intrahepatic, and mild pancreatic ductal dilatation. There was also infiltration of the medial wall of the second part of the duodenum and the posteroinferior wall of the first portion of the duodenum. Endoscopy showed duodenal narrowing due to the mass encroaching on the duodenum; hence malignancy was highly considered. However, a biopsy of left cervical lymphadenopathies seen revealed chronic granulomatous inflammation morphologically compatible with a tuberculous etiology. The patient underwent exploratory laparotomy with pancreatic head mass biopsy, where the frozen section revealed chronic granulomatous inflammation, possibly tuberculous in etiology, hence proceeded with gastrojejunostomy and cholecystojejunostomy. Postoperatively, the patient was stable and sent home with six months of anti-Koch medication, with a final diagnosis of pancreatic tuberculosis. Repeat MRCP revealed a resolution of the previously seen pancreatic head and body mass and biliary dilatation. Conservative management usually successfully alleviates symptoms and even the complete regression of mass lesions. The excellent response to anti-Koch’s medication makes it imperative that these patients are diagnosed early and managed appropriately to avoid unwarranted surgery and associated morbidity.

References

Auerbach O. Acute Generalized Miliary Tuberculosis. The American Journal of Pathology. 1944Jan;1(20):121–136.
Chaudhary P, Bhadana U, Arora MP. Pancreatic tuberculosis. Indian Journal of Surgery. 2015;77(6):517–24.

Disclosure

No conflict of interest was foreseen by the authors.

Introduction

Pancreatic cysts are a common finding in imaging studies, and, considering the different malignant potentials of mucinous and non-mucinous cysts, it is necessary to develop accurate methods and algorithms to differentiate between them. We conducted this study to compare the diagnostic performance of glucose levels and CEA levels in the diagnosis of mucinous pancreatic cysts.

Aims & Methods

We conducted a retrospective study of patients who underwent EUS-FNA of pancreatic cystic lesions between September 2020 and March 2023 at a tertiary referral center. We included patients whose glucose and CEA levels had been measured. Indicators of mucinous cysts include glucose levels less than 2.7 mmol/l and CEA levels greater than 192 ng/ml. It was compared to the final pathology (obtained after surgery or by EUS-FNB) result to determine their accuracy.

Results

	Non-mucinous	Mucinous
Gender (%male)	47.3%	33.3%
Age ( Median)	50.2	58.3
Cyst location
head	9	3
body	2	5
tail	8	4

A total of 31 patients were included in the study, 13 males and 18 females. The mean age was 55.7 years. Of the 31 patients, 12 (38.7%) were diagnosed with mucinous cysts (6 mucinous cystic neoplasms, 6 intraductal papillary mucinous neoplasms), and 19 (61.2%) were diagnosed with non-mucinous cysts (9 serous cystic neoplasm, 8 pseudocysts, 1 solid pseudopapillary neoplasm, and 1 lymphoepithelial cyst). There was a female prevalence in patients with mucinous cysts (8 females and 4 males) with a mean age of 59,6 years. From the cyst fluid analysis, the sensitivity, specificity, and accuracy of glucose in diagnosing mucinous cysts were 91.7%, 89.5%, and 90.3%, respectively. CEA’s sensitivity, specificity, and accuracy were 81.8%, 85.0%, and 83.9%, respectively.

Conclusion

In the diagnosis of pancreatic cystic lesions, glucose levels have high diagnostic performance with high sensitivity and accuracy. In contrast, CEA levels have a lower diagnostic performance. The findings of our study support the use of EUS-FNA and glucose levels in the diagnosis of pancreatic cystic lesions, as well as EUS-FNB to obtain histological specimens for a more accurate diagnosis of pancreatic cysts. Further studies are needed to validate these findings and explore the potential of other biomarkers in diagnosing and managing pancreatic cystic lesions.

Introduction

Ulcerative colitis (UC) is increasing in prevalence and incidence in Korea, and each patient shows a different course and treatment response. Since the 2000s, biologics have been developed and treatment options have diversified. Biologics and small-molecule therapeutics for immunological targets are currently under research and development. In the past, the goal was clinical improvement, including symptoms, but now endoscopic mucosal healing and, furthermore, the continuation of histological remission are gradually suggested. Accordingly, the purpose of this study was to identify clinical factors that could predict histological remission in patients receiving a first-line biologic agent, as well as confirm the patient's response to treatment and prognosis.

Aims & Methods

We retrospectively analyzed the medical records of 440 patients who had been diagnosed with UC and exposed to biologics for the first time in our hospital without using biologics at other hospitals between January 01, 2010 and December 31, 2022. Patients who did not undergo pre- and post-exposure endoscopy and biopsy or whose follow-up was discontinued were excluded. Clinical characteristics, blood tests, endoscopic findings, and pathological examination results of a total of 72 patients were collected. Endoscopic response was defined as a decrease in the Mayo Endoscopic Subscore (MES) compared to the score before the first exposure to the biological agent. Histological remission was defined as the result of no cryptitis, no crypt abscess, or no inflammatory cells observed on histological examination, and histological response was defined as remission in patients previously observed with active inflammation.

Results

The ratio of males to females was 53:19, and the median age at the time of diagnosis was 41 years. The average Mayo score at the time of diagnosis was 7.2, and the group with a histological response was 6.0, showing a statistically significant difference. The average albumin was 3.88 and was 4.06 in the histological response group, with a statistically significant difference. The median time to exposure to the first biologic was 1520 days. A colectomy was performed in three cases. Biologics were started with infliximab in 46.7% of patients, followed by adalimumab and vedolizumab in 22.7% and 21.3%, respectively. There was no statistical correlation between histological response and each biologic agent.
MES before exposure to biological agents was 50% in 2 and 44.4% in 3, but there was no statistical difference between each group. Multivariate logistic regression analysis was performed to identify predictors of endoscopic and histological responses after the first exposure to biological agents. As a result, it was confirmed that the Mayo score, ESR, and albumin had a causal relationship with the endoscopic response, respectively, and the odds ratio was 0.781, 1.051, and 3.319, respectively (p-value 0.044, 0.007, 0.049). In addition, it was confirmed that the Mayo score had a causal relationship with the histological response with an odds ratio of 0.796 (p-value 0.046).

Conclusion

This study confirmed that disease activity before treatment was a predictor of histological remission in UC patients using first-line biologics. It was confirmed that the histological response as well as the endoscopic response were well induced when the disease activity was low. Therefore, early escalation to biologics before the patient's condition worsens may be the basis for improving the overall prognosis.

References

Park, Sang Hyoung et al. “Clinical Characteristics and Long-term Prognosis of Elderly-Onset Ulcerative Colitis in a Population-Based Cohort in the Songpa-Kangdong District of Seoul, Korea.” Gut and liver vol. 15,5 (2021): 742-751. doi:10.5009/gnl20289
Park, Sunhee et al. “Histological Disease Activity as a Predictor of Clinical Relapse Among Patients With Ulcerative Colitis: Systematic Review and Meta-Analysis.” The American journal of gastroenterology vol. 111,12 (2016): 1692-1701. doi:10.1038/ajg.2016.418

Clinical Case Summary

A 25-year-old man, a law graduate, denied significant medical history, except for an appendectomy in 2014. He was diagnosed with chronic idiopathic ulcerative colitis in 2016 and was previously treated with mesalazine 4.5g every 24 hours. A colonoscopy in 2019 showed pancolitis Mayo 3 (Montreal S2-E3). Due to the lack of response to conventional treatment, prednisone cycles were initiated, and infliximab was started at a dose of 5mg/kg since 2019 with an adequate clinical response. On 12/24/2020, calprotectin was 5149 mcg/g.
In September 2021, he presented with asthenia, adynamia, dizziness, and unquantified fever, so he went to the hospital, where systemic inflammatory response syndrome was evident (tachycardia, fever of 39°C, and leukocytosis, dyspnea). Serial blood cultures and bacilloscopies were negative, and a chest CT scan showed a solid nodule-like pulmonary lesion in the right middle lobe (image 1). In November 2021, a thoracotomy with right middle lobectomy was performed, revealing abundant purulent material and a suggestive lesion of a lung abscess; it was positive for Nocardia farcinica, and histopathological results were positive for Nocardia spp. The patient subsequently developed cerebellar syndrome, and an MRI on November 5, 2021, showed cerebellar abscesses in the left hemisphere and hydrocephalus (image 1), requiring a ventriculoperitoneal shunt placement and surgical decompression, draining abscess, and isolating Nocardia spp.
Directed antibiotic therapy (trimethoprim-sulfamethoxazole) was started and continued until December 2021 with clinical improvement. Anti-TNF was discontinued, and mesalazine, steroid, and azathioprine were continued to maintain clinical remission of the disease without neurological and respiratory sequelae.

References

1. Abreu C, Rocha-Pereira N, Sarmento A, Magro F. Nocardia infections among immunomodulated inflammatory bowel disease patients: A review. World J Gastroenterol. 2015 Jun 7;21(21):6491-8. Doi: 10.3748/wjg.v21.i21.6491. PMID: 26074688; PMCID: PMC4458760.
2. Margalit I, Goldberg E, Ben Ari Y, Ben-Zvi H, Shostak Y, Krause I, Muhsen K. Clinical correlates of nocardiosis. Sci Rep. 2020 Aug 31;10(1):14272. Doi: 10.1038/s41598-020-71214-4. PMID: 32868850; PMCID: PMC7459281.
3. Garner O, Ramirez-Berlioz A, Iardino A, Mocherla S, Bhairavarasu K. Disseminated Nocardiosis Associated with Treatment with Infliximab in a Patient with Ulcerative Colitis. Am J Case Rep. 2017 Dec 21;18:1365-1369. Doi: 10.12659/ajcr.906391. PMID: 29263313; PMCID: PMC5742452.

Disclosure

Patients with Inflammatory Bowel Disease (IBD) undergoing anti-TNFa treatment are at risk of opportunistic infections, including nocardiosis, caused by Nocardia, gram-positive bacteria that can cause local (lung, skin, and brain) or disseminated infections. In the literature, only 11 cases of nocardiosis related to anti-TNFa have been reported¹.TNFa is an important mediator of inflammation for granuloma formation, and Nocardia spp. is one of the pathogens that generate these granulomas². The diagnosis of nocardiosis should have a high clinical suspicion, especially in patients with risk factors, as it is one of the least reported opportunistic infections, in our case, with the use of anti-TNF in the context of IBD. There are no official reports on prevalence and incidence in the literature².
The most frequent sites of dissemination are the lungs and skin, leading to the central nervous system and any organ³. The diagnostic confirmation is made through pathogen isolation in a clinical sample, which was performed through histopathology of a pulmonary segment².
Treatment is based on antimicrobial therapy and restoration of complications, in our case, a segmentectomy was necessary due to pulmonary infection, and a ventriculoperitoneal shunt placement was necessary due to central nervous system involvement. TMP/SMX has been considered the first-line antimicrobial for 50 years², but targeted therapy based on isolation is recommended, with alternatives including amikacin, carbapenems, and third-generation cephalosporins². The response to TMP/SMX was appropriate in this case.