Introduction

The use of infliximab (IFX) is limited by low treatment persistence. Proactive therapeutic drug monitoring (pTDM) has been shown to increase the treatment persistence in inflammatory bowel disease (IBD) patients but the real-life data evaluating effectiveness, safety and costs of this approach are scarce.

Aims & Methods

The aim of this study was to assess survival on treatment, safety and costs of pTDM of IFX in the treatment IBD.
IBD patients who started IFX in a referral centre using pTDM between January 2018 and March 2021 were included. The main outcomes were treatment persistence, adverse events and incremental costs of pTDM.
IFX trough levels were assessed in the week 14 and subsequently every six months by commercially available ELISA kit (Ridascreen R-Biopharm) and the intensification of treatment the cut-off of 3μg/ml was used.
Costs related to the measurements of levels and the costs of intensified treatment were calculated. The costs of pTDM were compared costs of a modelled cohort using reactive TDM (rTDM) based on the data from the same cohort. The model used arbitrarily determined intensification regimen to 5mg/kg of IFX every 4 weeks in pharmacokinetically determined clinical or endoscopic loss of response. The calculation was performed for the first year of treatment.

Results

Overall, 99 patients with IBD were included (58 men – 59%; mean age 39,96 years, minimum-maximum, 20-73 years; 64% patients with Crohn´disease; mean disease duration 103 months, minimum – maximum, 8-402 months).
The treatment was intensified in 57 patients (58%). Overall treatment survival with pTDM was 87% at 6 months, 77% at one year, 66% at two years and 60% at both, the third and fourth year of treatment. There were no differences between patients on conventional regimen vs. intensified regimen with regards to adverse events.
The costs related to pTDM in this cohort of 99 patients were € 90 306,56 while the costs of the modelled cohort using rTDM were € 24 846,30. The overall incremental costs were thus € 65 460,26 with mean costs per patient for the first year of treatment of € 661,21.

Conclusion

Proactive TDM of IFX results in a steady 60% treatment persistence beyond the second year of treatment with no impact on the safety.
In the context of this solid treatment persistence, the incremental costs related to proactive TDM seem negligible when considering the costs of alternative biologicals used in case of loss of response to IFX.

Disclosure

nothing to disclose

Introduction

Anemia represents the most frequent extra-intestinal manifestation of Inflammatory Bowel Disease (IBD) and it is most frequently caused by iron deficiency.
Despite iron replacement therapy, most IBD patients fail to recover from anemia thus contributing to fatigue and reduced quality of life. Many genetic mutations cause iron-deficiency refractory anemia (IDRA), and their frequency in IBD patients remains unknown. Furthermore, the great prevalence of thalassemic trait in Sardinian IBD patients may further complicate the management of anemia in this population.

Aims & Methods

Aim: To describe the prevalence of IDRA-related genetic mutations in Sardinian IBD patients and their role in the management of anemia.
Methods: All IBD patients matching the criteria for the diagnosis of IDRA, according to WHO criteria, and without known causes of anemia other than IBD, were included in the study. Blood analysis to evaluate Hb, MCV, Tsat, MCH, ferritin, serum iron, vitamin D, vitamin B12, folate, CRP and stool analysis for fecal calprotectin were performed at T0, after 4 (T4) and after 8 (T8) weeks. Iron-replacement therapy was given to all patients. All patients were genetically tested for mutations in ABCB7, ALAS2, HSPA9, MPL, TMPRSS6, TRNT1, GLRX5, SLC11A2, SLC19A2, SLC25A38, YARS2, HBA1, HBA2, HBB, PUS1 genes. Therapy response/remission and safety were evaluated at T4 and T8. The presence of genetic mutations and their correlation with therapy response at T8 was evaluated as primary endpoint and analyzed by correlation tests (Chi-squared and Fisher’s exact test).

Results

Twenty-two IBD patients matching the inclusion/exclusion criteria were included in the study. At baseline, mean Hb concentration was 10.86 ± 1.18 gr/dL, mean MCV 71.64 ± 9.61 fL, MCH 23.55 ± 3.49, and median ferritin concentration 12.75 ng/ml (range 3.8-93.3). At T8, 19/22 (86%) pts were therapy failure, 3/22 (14%) were
responders, while 8/22 (36%) had anemia resolution. 8/22 (36%) pts carried genetic mutations: 3/22 (13.6%) had single HBB gene mutation, 1/22 (4.54%) single ALAS2, 2/22 (9.09%) double HBA1, 1/22 (4.54%) had both HBA1 and HBB, and 1/22 (4.54%) had both HBA2 and ALAS2 gene mutations. The presence of genetic mutations was significantly correlated to iron-replacement therapy failure at T8 (p=0.0423). No biochemical parameter or clinical disease characteristics were found to be predictors of therapy response through logistic regression analysis. No sides effects were recorded during the study period.

Conclusion

The presence of unknown thalassemic trait and other allele variants involved in iron metabolism may explain the iron-replacement therapy refractoriness in Sardinian IBD patients.

Disclosure

no conflict of interest to declare

Clinical Case Summary

Extra intestinal digestive involvement of tuberculosis (TB) remains a rare entity, even in endemic countries.3 cases of extra intestinal digestive TB in immunocompetent patients are reported.
Case 1: A 50-year-old man was admitted for exploration of weight loss and weakness, with chronic abdominal pain. A computed tomography (CT) scan of the abdomen showed multiple hypodense hepatics and splenic nodules; an ultrasound-guided percutaneous liver biopsy was performed. The patient was diagnosed to have primary hepatosplenic TB. Images:
1:CT scan:multiple lesions in the liver and spleen
2:Liver tissue showing granulomatos reaction)
Case 2: A 24-year-old woman,admitted for exploration of chronic epigastralgia.Abdominal and pelvic CT scan and pancreaticobiliary Magnetic Resonance Imaging (MRI)showed a mass at the isthmus and tail of the pancreas associated with adenopathies.The endoscopic ultrasound (EUS)showed a cystic lesion at the pancreatic corporal-caudal junction. Given the strong suspicion of a pseudo papillary and solid tumor of the pancreas,a caudal splenopancreatectomy was decided. Intraoperatively, exploration revealed,whitish pinhead-sized lesions disseminated over the entire pancreatic parenchyma,suggesting pancreatic TB.An anatomopathological examination of an adenopathy confirmed the diagnosis of TB. Images:
1:MRI showing a mixed lesion in the pancreas
2:EUS image showing the heterogeneous lesion of the pancreas)
Case 3: a 28-year-old man, was admitted for exploration of abdominal pain with fever and weight loss.The physical examination found an abdominal tenderness and hepatomegaly.Hepatic nodular lesions were revealed on CT and MRI.The diagnosis of hepatic tuberculosis was confirmed after anatomopathological analysis of the biopsies of the hepatic nodules obtained during laparoscopy. images:
1: Abdominal CT scan:multiple hypodense hepatic lesions
2: A hepatic MRI:a dysmorphic liver,with heterogeneous lesions)

Introduction

Ulcerative colitis (UC) is a chronic and relapsing disease for which the number of biological therapies available are increasing over the years. Data comparing the effectiveness of a second anti-TNFɑ (aTNF) and the switch to a different mechanism of action (MoA) such as Ustekinumab (UST), Vedolizumab (VDZ), Filgotinib or Tofacibinib (JAK) is lacking.

Aims & Methods

We performed a retrospective and multicenter study (6 Andalusian sites). Patients diagnosed of UC who had failed a first biological therapy with an aTNF and started a second-line biological therapy with another aTNF or a different MoA (UST, VDZ, JAK) were included. Clinical response and remission were assessed at weeks 16 and 52. The aim of our study was to evaluate the effectiveness of a second-line biological therapy with aTNF compared to a different MoA after a first aTNF failure.

Results

185 UC patients were included. There were no differences in the demographic data except for disease duration (9 years with MoA vs 13 years in aTNF, p=0.02). As first aTNF, infliximab (IFX) was the most common in both groups (49% MoA group, 56% second aTNF), followed by adalimumab (ADA) (48% MoA group, 33% second aTNF). In the second aTNF group, immunomodulators were significatively more used (60% vs 38%, p=0.003). There were no differences in the concomitant use of steroids. 80 patients received a different MoA (37 VDZ, 24 UST, 19 JAK) and 105 a second aTNF (34 IFX, 60 ADA, 11 golimumab). At week 16, 52% of patients were in clinical response (70% with another MoA vs 54% with second aTNF, p=0.07; IFX 65%, ADA 53%, VDZ 68%, UST 71%, JAK 74%, p=0.07), being 15.6% more likely to achieve response with another MoA. Clinical remission at week 16 was obtained by 36% (39% with another MoA vs 33% with second aTNF, p=0.6; IFX 47%, ADA 30%, VDZ 35%, UST 46%, JAK 37%, p=0.1). At week 52, 48% achieved clinical response (51% with another MoA vs 45% with second aTNF, p=0.8; IFX 50%, ADA 42%, VDZ 49%, UST 54%, JAK 53%, p=0.5) and 39% were in clinical remission (40% with another MoA vs 38% with second aTNF, p=0.53; IFX 50%, ADA 32%, VDZ 35%, UST 38%, JAK 53%; p=0.06). When the effectiveness is analyzed by first aTNF used, independently of the aTNF, subsequent use of a different MoA achieves better results although not significant compared to a second aTNF. Partial Mayo and calprotectin showed a significant decrease at weeks 16 and 52 in both groups. Hemoglobin and albumin levels remained similar during follow-up in both groups.

Conclusion

Second-line biological therapy is effective regardless of biological therapy used in UC, but switching to a different MoA tend to achieve better results in terms of clinical response and remission compared to a second aTNF.

Clinical Case Summary

A 62 y/o male complaining from epigastric pain, constipation, vomiting and eructation for two months and CT abd revealed irresectable pancreatic head mass 4.5x4.5 cm encasing PV and SMV with duodenal invasion. Ryle decompression was done before EGD, duodenal obstruction was noted and biopsy showed duodenitis (stasis induced). EUS-FNB confirmed well differentiated AC. Duodenal stenting was successfully performed with improving symptoms.
After one week patient complained from weakness and abnormal gait, examination showed normal vital signs, bilateral lower limb edema and patient was lethargic. Three days after, the patient became confused (GCS 12), so he was admitted to ICU.
CT brain was unremarkable. Lab investigations showed the following:
Na 130, K 4.1, Ca 7.8, Phos 2.8, Mg 2.6, Alb 2.9
Refeeding injury was suspected and TPN was started by the ICU team. No improvement of the consciousness was achieved and patient caught chest infection, developed sepsis and died.
Discussion: Refeeding syndrome is a serious complication that can be easily missed [1] in upper GI malignant obstructions with prolonged decreased oral intake along with the malignancy cachexia status. These obstructions may need surgery or stenting to regain patency and without cautious monitoring of the nutrients repletion rate either enteral or parenteral this will lead to fluid and electrolyte disturbance (Fluid balance abnormalities, Abnormal glucose metabolism, Vitamin deficiency, e.g., vitamin B1 (thiamine), Hypophosphatemia, Hypomagnesaemia and/or Hypokalemia) [2] with symptoms ranging from vague up to life threatening conditions like disturbed conscious level and heart failure. Our patient had high risk of developing refeeding syndrome due to caloric deprivation secondary to duodenal obstruction with development of the symptoms after stenting and restarting oral intake.
Conclusion: Nutritionist counseling after GI stenting of upper GI malignant obstructions is needed to avoid refeeding syndrome.

References

[1] Reber, E., Friedli, N., Vasiloglou, M.F., Schuetz, P. and Stanga, Z., 2019. Management of refeeding syndrome in medical inpatients. Journal of clinical medicine, 8(12), p.2202.
[2] Crook, M.A., Hally, V. and Panteli, J.V., 2001. The importance of the refeeding syndrome. Nutrition, 17(7-8), pp.632-637.

Introduction

Patients suffering from ulcerative colitis (UC) have reduced life qualities and an increased risk of developing cancer. Current treatment options are limited and have a ceiling effect with remission rates of ~35%. A possible reason is the multi-factorial aetiology, which are associated with an overactivation of the immune system and a dysbiosis of the gut microbiome. An important step towards a better understanding is the characterization of epithelial lesions. Their severity is classified by the Mayo score system based on their macroscopic appearance. While previous studies analysed cellular changes within the colon in UC patients, a detailed characterization of different UC-associated lesions are still missing, which is the aim of our study in collaboration with Sanofi Pharmaceuticals.

Aims & Methods

We recruit patients with active disease at our endoscopy unit and collect different biopsies from multiple regions within these patients to compare the reproducibility of single cell RNA sequencing (scRNAseq) results of similar appearing lesions within and between patients. For the sample preparation, we performed a cellular enrichment step for immune, epithelial and stromal cells before performing 10x scRNAseq to obtain equal numbers for each cell fraction from every sampled area. Additionally, we collected stool samples and endoscopic brushes to determine the associated microbial communities by 16S rRNA sequencing.

Results

Our cellular isolation strategy allows successful recovery of fibroblast, epithelial and immune cell fractions from each lesion. All expected epithelial cell types as previously described are detected in our dataset as well. Moreover, our experimental setup to obtain comparable numbers of fibroblasts, epithelial and immune cells enables us now to investigate cell-cell communication differences within different Mayo score lesions. For example, CXCL signals increased with the severity of macroscopic lesions and involves multiple cell types. Additionally, we are in the middle of correlating microbial diversity with the corresponding disease conditions.

Conclusion

Our results provide exciting insights into cell-cell communications at an unprecedented depth, which identifies aberrant signalling pathway that may contribute to treatment failure in the clinics.

Disclosure

We have nothing to disclose