Introduction

The number of patients with inflammatory bowel disease (IBD) refractory to different biologic classes and small molecules is growing. Combining mechanisms of action seems to be the key to breaking the therapeutical ceiling; however, the available evidence is still limited and of low quality.

Aims & Methods

We conducted a systematic review and meta-analysis to summarize the available data on the safety and effectiveness of different combinations of biologics and small molecules in Crohn's disease, ulcerative colitis, and indeterminate colitis.
Through a systematic search of multiple electronic databases until March 1, 2023, we included studies with two or more patients on dual biologic therapy or in combination with small molecules due to active intestinal disease.
We reported effectiveness as pooled rates of clinical and endoscopic response and remission. Safety was assessed as pooled rates of adverse events and serious adverse events for each combination. The quality of evidence was rated according to the Critical Appraisal Skills Programme checklist.

Results

We included 28 studies - 2 randomized controlled trials and 26 observational studies - with 499 patients on 7 different combinations (Anti-TNF + Vedolizumab/Ustekinumab/Tofacitinib/Natalizumab/Goselkumab or Vedolizumab + Ustekinumab/Tofacitinib). The most common was tumor Anti-TNF & anti-integrins (n=96).
In patients mostly refractory to monotherapy due to active intestinal disease, combination therapy resulted in pooled clinical and endoscopic remission rates of 48% (CI 0.44-0.52) and 32% (CI 0.26-0.39), respectively. Pooled clinical and endoscopic response rates were 76% (CI 0.65-0.85) and 52% (CI 0.46-0.58), respectively.
Pooled serious adverse event rates (SAE) were 9% (CI 0.06-0.11), with Anti-TNF + Ustekinumab (n=19)/Natalizumab (n=52) and Ustekinumab + Tofacitinib (n=22), being the safest options with no registered SAE.
Heterogeneity was significant only for pooled rates of adverse events. The certainty of the evidence was low due to the nature and inconsistencies between the included studies. Most of the studies failed to report the outcomes based on the disease subtype and specify which biological agent was used when an anti-TNF was part of the combination. Only one study had a control arm with monotherapy.

Conclusion

Combining Biologics and Small Molecules appears safe and possibly effective in patients with IBD. New trials with higher-quality data will be detrimental to generalizing access to this approach.

References

Alayo QA, Fenster M, Altayar O, Glassner KL, Llano E, Clark-Snustad K, Patel A, Kwapisz L, Yarur AJ, Cohen BL, Ciorba MA, Thomas D, Lee SD, Loftus EV Jr, Fudman DI, Abraham BP, Colombel JF, Deepak P. Systematic Review With Meta-analysis: Safety and Effectiveness of Combining Biologics and Small Molecules in Inflammatory Bowel Disease. Crohns Colitis 360. 2022 Feb 10;4(1):otac002. doi: 10.1093/crocol/otac002. PMID: 35310082; PMCID: PMC8924906.
Mas, E.B.; Calvo, X.C. Selecting the Best Combined Biological Therapy for Refractory Inflammatory Bowel Disease Patients. J. Clin. Med. 2022, 11, 1076. https://doi.org/10.3390/jcm11041076
Ahmed W, Galati J, Kumar A, Christos PJ, Longman R, Lukin DJ, Scherl E, Battat R. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2022 Mar;20(3):e361-e379. doi: 10.1016/j.cgh.2021.03.034. Epub 2021 Mar 31. PMID: 33798711.

Introduction

Natural history of anal stricture observed in Crohn’s disease (CD) remains poorly known, especially in pediatric onset CD.

Aims & Methods

All patients with a diagnosis of CD before the age of 17 years between 1988 and 2011 within the population-based registry EPIMAD were followed retrospectively until 2013. At diagnosis and during follow-up, the clinical and therapeutic features of perianal disease were recorded.

Results

Among the 1,007 included patients (females, 451 (44.8%); median age at diagnosis 14.4 years (IQR, 12.0-16.1)), one (0,1%) had an anal stricture at diagnosis and 26 (2.6%) during follow-up. Cumulative incidence of anal stricture at 5 and 10 years from diagnosis was 0.6% (95%CI, 0.1-1.1) and 1.4% (95%CI, 0.5-2.3), respectively. Twenty-five (n=25/27, 92.6%) patients had at least one episode of anal ulceration or fistulizing perianal Crohn’s disease (pCD). In multivariable analysis, the presence of extra-intestinal manifestations (HR 2.3 (95%CI, 1.1-4.9), p=0.0378), colonic location (L1 vs L3 HR 0.0 (95%CI, 0.0-na), L2 vs L3 HR 1.2 (95%CI, 0.5-2.7), p=0.0246) and history of fistulizing pCD (HR 7.6 (95%CI, 3.2-17.9), p<0.0001) were significantly associated with the onset of anal stricture. Eleven (40.7%) patients needed at least one dilatation. After a median follow-up of 6.2 years (IQR, 2.4-10.6), after anal stricture diagnosis, healing was observed only once. One patient (3.7%) had an anal cancer seven years after stricture diagnosis and nine (33.3%) patients needed a stoma. Anal stricture was significantly associated with the need of stoma (HR 5.8, 95%CI 2.3-14.3), p=0.0002).

Conclusion

The occurrence of anal stricture is an infrequent event in pediatric onset CD, since only 1.5% of patients will present an event after 10 years. Anal stricture increased the risk of stoma by a factor of 5.

Clinical Case Summary

A 70-year-old patient with diabetes mellitus and cholecystectomy performed six months earlier was admitted to the emergency department for generalized abdominal pain, hyporexia and weight loss.
An abdominal CT scan showed a solid-cystic pancreatic lesion suggestive of mucinous neoplasia, together with peritoneal nodules in the right paracolic gout. In view of the suspicion of malignancy, an echoendoscopy with fine needle aspiration puncture (EUS-FNA) was performed, identifying an irregular lesion with heterogeneous and hypovascular ultrastructure in the pancreatic neck-body and a discrete dilatation of the main pancreatic duct. Finally, the histological study didn´t show neoplastic cells.
Suddenly the patient experienced a clinical worsening with severe pain and high fever. Laboratory tests showed a progressive increase in C-reactive protein and leukocytosis with left shift. In a control CT scan, a reduction in the size of the pancreatic lesion is observed, together with an increase in the peritoneal lesions which present a polyglobulated contour, hypercapillary margins and rarefaction of the surrounding fat. These finding suggesting the presence of peritoneal abscesses secondary to dropped gallstones. After broad-spectrum antibiotic therapy, the intra-abdominal abscesses improved radiologically, but the collection persisted in the right posterior pararenal space which was drained under ultrasound control with subsequent disappearance of fever and normalization of analytical parameters.
Dropped gallstones occur in approximately 7% of cholecystectomies. The secondary granulomatous reaction in paucisymptomatic patients can simulate peritoneal tumor processes in imaging tests, being one of the adverse effects described in relation to this pathology. In our case, the concomitant presence of peritoneal lesions together the pancreatic lesion oriented the initial case as a malignant process; however, the patient's evolution were key to the final diagnosis.

Introduction

Cholangiocarcinoma (CCA) prevalence is high in East and Southeast Asia, especially in northeast Thailand. The first line of treatment for unresectable CCA is systemic chemotherapy which a median OS of less than 1 year under palliative systemic therapy. Albumin-Bilirubin (ALBI) prognosis score is the new method for the evaluation of liver performance status and prediction of treatment outcome but there is a lack of data in CCA patients.

Aims & Methods

Aim: To study the association of overall survival and ALBI prognostic score in unresectable CCA patients who received systemic chemotherapy.
Methods: This retrospective cohort study was conducted in Maha Chakri Sirindhorn Medical Center, Thailand. Demographic data, Clinical information, Laboratory profile, and survival analysis were extensively reviewed in the patient who received systemic chemotherapy from 2012 - 2022. All patients were monitored for at least 1 year after initial treatment with chemotherapy or until death.

Results

​69 patients of Unresectable CCA received systemic chemotherapy enrolled in this study. Most of the patients were men (45/69, 65.22%) and Intrahepatic type CCA (55/69, 79.71%). 17 patients (24.6%) need Biliary drainage before systemic chemotherapy which median pre-drainage TB was 11.35 mg/dL (10.7 – 20.6). Most ALBI prognostic score were group 2 (37/69, 53.6%) and anemia was significantly in ALBI 2 group (81.08%, P <0.001). The median overall survival was 10.23 months and the median progression-free survival was 5.77 months. Significantly better overall survival of the ALBI 1 group compared with the ALBI 2 group (ALBI 1, 13.76 months; ALBI 2, 6.33 months; log-rank test, P <0.001). The estimated 6, 12, 18, and 24-month survival rates were 72.46%, 40.58%, 18.84%, and 8.70%, respectively, whereas the estimated progression-free survival rate at 6, 12, 18, and 24 months were 47.83% and 10.14%, respectively.

Conclusion

ALBI prognosis score may serve as a surrogate marker in predicting the overall survival and progression-free survival of CCA patients who received Systemic chemotherapy.

References

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Disclosure

There is no any conflict of interest in this study

Introduction

Infection with SARS-CoV-2 leads to pronounced changes in the intestinal microbiome and also decay of tryptophan that are both related to disease severity. Supplementation of tryptophan metabolism using ileocolonic-release nicotinamide may stabilize the microbiome and alleviate COVID-19 symptoms.

Aims & Methods

This prospective, double-blind, randomized, placebo-controlled trial evaluated safety and efficacy of a 4-week intervention with a novel oral formulation of nicotinamide (1,000 mg/d) in symptomatic, unvaccinated, non-hospitalized outpatients with PCR-proven early COVID-19. The primary outcome was full recovery from reduced physical performance after 2 weeks in the prespecified symptomatic primary analysis population with at least one risk factor for severe COVID-19. Stools from a part of the patients (4 timepoints) were submitted to 16S rRNA (n=70) and shotgun metagenomics (n=18) sequencing.

Results

Screening of 7,013 patients resulted in randomization of 900 participants (nicotinamide or placebo (1:1), from which 867 received the investigational product and 500 qualified for the acute disease analysis population. 110 of 191 patients (57.6%) receiving nicotinamide and 80 of 188 patients receiving placebo (42.6%) recovered from their performance drop at week 2 (absolute difference, 15.0 percentage points; odds ratio, 1.33; 95% confidence interval, 1.03 to 1.70; P=0.004). Nicotinamide was also superior in the secondary endpoints ability to perform normal activities (P=0.009) and shortness of breath (P=0.012). Substantial effects on gut microbiome constitution were seen counteracting COVID-19 related changes. Reduction of tryptophan biosynthesis in the microbiome in placebo patients was restored and NAD salvage pathways were activated in nicotinamide-treated individuals. No relevant safety signals were observed.

Conclusion

Oral treatment with nicotinamide stabilized the gut microbiome against COVID-19 related changes and led to faster recovery of physical performance in symptomatic patients at risk for severe Covid-19. (Funded by the German Research Foundation [DFG], the State of Schleswig-Holstein and the UEG Research Prize; ClinicalTrials.gov number: NCT04751604)

Disclosure

SS reports indirect stock ownership in Gerion Biotech GmbH as well as consulting and personal fees from AbbVie, Allergosan, Amgen, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Ferring, Fresenius, Galapagos/Gilead, HIKMA, I-Mab, Janssen, Lilly, Morphic, MSD, Mylan, Pfizer, Prometheus, Protagonist, Provention Bio, Sandoz/Hexal, Takeda, and Theravance.
GHW is employed part-time by CONARIS Research Institute AG (Kiel, Germany).
TB reports consulting fees, honoraria or other support from AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Merck, MSD, Novartis, Pfizer, and Roche.
KA reports consulting fees, honoraria or other support from AbbVie, Falk, Galapagos, Janssen, Pfizer, and Takeda.
ML reports a lecture honorarium and travel support by AstraZeneca.
PR reports stock ownership in Gerion Biotech GmbH and consulting fees from Takeda.

Introduction

The overall burden of B / D and C viral hepatitis remains substantial, despite the major advances in the prevention and treatment of patients in recent years, due to comorbidities and complications associated with liver disease. In this context, the national screening program LIVE (RO) 2 aims to further assess all patients identified as positive for one of the hepatitis B / D / C viruses.

Aims & Methods

The study aimed to identify fortuitous pathologies discovered in patients with chronic viral B / D / C infection diagnosed in the LIVE (RO) screening program 2. We conducted a prospective study that included people from vulnerable groups (poor, uninsured, rural people, people in foster care, homeless, Roma population, people with disabilities, and suffering from alcohol or drug addiction) in different areas of North-Eastern Romania, between July 2021 - April 2023, during the national screening program LIVE (RO) 2-EAST. We also investigated the presence of newly discovered conditions in patients who tested positive and directed to the Institute of Gastroenterology and Hepatology in Iasi for the staging of liver disease and the establishment of antiviral treatment.

Results

The study group included 1176 patients, of which 422 men (35.8%) and 754 women (64.1%), aged between 35 and 83 years, with a mean age of 56.32 years. The predominant source of origin was rural (73.1%). Of the patients with positive RDTs, 635 (53.9%) patients were detected with HBsAg, 521 (44.3%) patients with anti-HCV antibodies, and 20 (1.7%) patients with anti-HVD antibodies. Of these, 215 patients (18.2%) were diagnosed with a new pathology associated with B / D / C viral infection. The most common pathologies discovered incidentally were liver cirrhosis (94, 43.7%), liver cysts (35, 16.2%), liver hemangiomas (29, 13.4%), gallstones (24, 11.1%), type II diabetes mellitus (T2DM) (15, 6.9%), uterine fibroids (9, 4.1%), hepatocellular carcinoma (7, 3.2%), choledochal lithiasis (2, 0.9%). In addition, the presence of fortuitous pathologies was higher among patients with HBV infection than in those with HCV infection (65.3% vs. 42.1%, p = 0.012). Among the risk factors associated with hepatocellular carcinoma (HCC) are chronic alcohol consumption (43%, compared to 19% in the group of patients without HCC), and the association of T2DM in 3 patients (31%, compared to 10% in the group of patients with HCC).

Conclusion

Patients with chronic B / D / C viral infection had a high prevalence of incidentally detected comorbidities, which necessitates the need for public health policies in vulnerable groups to promote access to existing health services to reduce the future burden of chronic diseases but also secondary complications of chronic liver disease.

Introduction

Hepatitis C has an important global impact in terms of morbidity, mortality and economic costs, being a real public health problem worldwide. The efficacy of the new direct-acting antivirals treatment determined the World Health Organization (WHO) to adopt the ambitious strategy for Global Health Sector on Viral Hepatitis in 2016, having as main objective to eliminate hepatitis C virus (HCV) by 2030. In response to this challenge, several countries have already initiated the micro-elimination strategy as part of the global C virus eradication program.

Aims & Methods

We aimed to evaluate the prevalence of HCV infection and risk factors in a Romanian village population-based screening and link these data to the antiviral treatment.We conducted a prospective study from 1 March2022 to 28 February 2023, based on a strategy as part of a project designed to educate, screen, treat and eliminate HCV infection in all adults, in a village located in Northeastern Romania. All demographic data and risk factors for HCV infection were collected through a questionnaire.

Results

In total, 3507 subjects were invited to be screened by rapid diagnostic orientation tests. Overall, 2945 (84%) subjects were tested, out of whom 78 (2.64%) were found with positive HCV antibodies and were scheduled for further evaluation in tertiary center of gastroenterology/hepatology, in order to be linked to care. A number of 66 (85%) subjects presented for evaluation and 55 (83%) had HCV RNA detectable. Of these, 54 (98%) completed antiviral treatment and 53 (99%) obtained sustained virological response. The main risk factors associated with chronic HCV infection were family history of HCV (OR=2.23, 95%CI=1.37–3.5, p<0.0001), professional exposure to blood products (OR=0.25, 95%CI=0.11-0.53, p<0.0001), blood transfusions performed before 1992 (OR=3.21, 95%CI=2.25-4.52, p<0.0001), abortions undergone before 1990 (OR=1.35, 95%CI=1.02-1.9, p<0.023), multiple surgical interventions (OR=1.32, 95%CI=1.05-1.72, p<0.038) and sharing personal hygiene objects (OR=1.45, 95%CI=1.12-1.73, p<0.002).

Conclusion

The elimination of hepatitis C worldwide has become a reality, with higher chances of success if micro-elimination strategies based on mass screening are adopted. At the same time, sustained effort it required from all. The development of screening programs can facilitate the cascade of care from diagnosis to treatment of all patients and the achievement of WHO objectives.