Introduction

Chronic constipation (CC) is one of the most frequent non-motor features of Parkinson’s Disease (PD). Previous studies highlighted the association of CC with PD duration and severity [1]. Furthermore, gut microbiota changes and brain-gut-axis (BGA) dysregulation are common in PD and these alterations are related with clinical manifestations [2,3]. For this reason, probiotics, balancing the gut microbiota, are emerging as a potential therapeutic approach in PD patients.

Aims & Methods

Objective: To evaluate the patients’ satisfaction rates as well as gastroenterological and neurological effects of the administration of a synbiotic in PD patients with CC.
Methods: This study enrolled patients with stable PD who fulfilled Rome IV Criteria for CC or irritable bowel syndrome with constipation (IBS-C). Patients received a synbiotic treatment (Enterolactis ® duo, 4 sachets/day, containing probiotic Lactobacillus casei and prebiotic inulin) for 12 weeks. Two primary endpoints were chosen to monitor the satisfaction with therapy (SWT). SWT was defined when patients were satisfied (satisfaction score >4 on a 7-point Likert scale) or improved after therapy (increase in the global rating of change scale of at least two points on a -7 to +7 visual analogue scale). In addition, a gastrointestinal (GI) evaluation with the Patient Assessment of Constipation-symptoms questionnaire (PAC-SYM), number of complete bowel movements per week, Bristol stool Scale (BSS) were calculated before and after the treatment. The neuropsychological evaluation was performed by the Montreal Cognitive Assessment (MoCA), Movement Disorder Society-Sponsored Revision of Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), SCales for Outcomes in Parkinson’s disease - Autonomic Dysfunction (SCOPA-AUT), Toronto Alexithymia Scale (TAS-20), Reading the Mind in the Eyes Test (RMET), Parkinson Anxiety Scale (PAS), State-Trait Anxiety Inventory (STAI-Y), Beck Depression Inventory (BDI II), Hamilton depression rating scale (HAM-D) pre- and post-intervention.

Results

30 patients (10 F) were consecutively enrolled. Satisfaction >4 (endpoint 1) significantly changed from 17% to 60% patients after treatment, p = 0.002. The calculated satisfaction score significantly increased from 4(1) to 5(2) (median (IQR), p = 0.003. Improvement after treatment (endpoint 2) was achieved by 83% of patients. The Global Rating of Change Score changed significantly from 0(3) to 4(2)(median (IQR), p < 0.001. Moreover, a beneficial effect of treatment was shown on GI symptoms. Specifically, PAC-SYM Questionnaire score changed from 1.42(0.94) to 0.91(0.77), p < 0.001, number of complete bowel movements per week from 3(3.5) to 5.5(4.1) p < 0.001 and Bristol stool Scale (BSS) from 2(2) to 3(2) p < 0.001. After treatment PD patients performed better in motor and non-motor features. Specifically, the scores (median (IQR) of TAS-20 significantly changed from 55.0 (22) to 49.5 (21), p=0.03, SCOPA-AUT from 17.0 (7) to 13.5 (10), p = 0.002, MDS-UPDRS part 1 from 13.5 (13) to 9.0 (6), p = 0.001, HAM-D score from 12.5(10) to 9.0 (12), p = 0.045. PAS-A showed a trend towards significance from 7.0(6) to 5.0(7), p = 0.06.

Conclusion

Our results showed that a considerable number of PD patients with CC or IBS-C were satisfied with their defecation after treatment. GI symptoms as well as motor and non-motor features in PD patients improved. Our data suggest that the addition of a synbiotic Enterolactis ® duo may be a useful therapeutic approach in PD possibly acting on the gut-brain-gut axis.

References

References
[1] Krogh K, Ostergaard K, Sabroe S, Laurberg S. Clinical aspects of bowel symptoms in Parkinson’s disease. Acta Neurol Scand. 2008;117(1):60-64.
[2] Shen T, Yue Y, He T, Huang C, Qu B, Lv W, Lai HY. The Association Between the Gut Microbiota and Parkinson’s Disease, a Meta-Analysis. Front Aging Neurosci. 2021 Feb 12;13:636545.
[3] Scheperjans F, Aho V, Pereira PA, et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord. 2015;30(3):350-358.

Introduction

Tofacitinib is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC). The recommended induction scheme is 10 mg twice daily (BID) for at least 8 weeks followed by a maintenance dose of 5 mg BID. However, some patients require 10mg bid, for 16 weeks at the induction phase. Our study aimed to assess the demographics and disease characteristics of such patients and their outcome at 24 weeks.

Aims & Methods

This was a multicenter, retrospective, observational study which included patients with moderate to severe UC, who received induction therapy with Tofacitinib 10mg bid for a 16-week period. Data were collected between July 2018 and November 2022. The primary objective was disease outcome, defined as clinical remission and/or the need of steroids. Secondary outcomes were treatment withdrawal, treatment de-escalation and adverse events.

Results

In total 31 patients, are currently enrolled in our study, from 10 IBD centres [males: 51.6%, mean age at study entry: 40.0 years, median disease duration: 7 years]. Patient demographic and clinical characteristics at baseline are shown in table 1. Four patients (12.9%) discontinued treatment before week 24, due to inadequate response. De-escalation of dosing to 5mg bid tofacitinib was attempted in 13 of 27 patients (48.1%) and was successful in 7 patients (53.8%) who maintained clinical response until week 24 of the study. Of the other 6 out of 13 patients, 6 patients received again the higher dose (10 mg bid) and regained response and only one patient discontinued treatment. Overall, 85.7% (6/7) of the patients who received tofacitinib 5mg bid and 66.7% (14/21) who received 10mg bid at 24 weeks, had received more than one biologic prior to tofacitinib (P=0.34). At week 24, the partial Mayo score was available in 26 patients; 13 patients were in steroid-free clinical remission (pMayo <2). Twelve patients had mild active disease (pMayo 2-4) and 9 of them had stopped steroids. No major adverse events were observed during the entire observation period.

Conclusion

In a real-world setting, a 24-week treatment with tofacitinib 10mg BID is safe and the majority of patients achieve clinical remission and manage to stop steroids. De-escalation at 5mg bid is successful in more than half of them. We prospectively follow up our cohort to investigate whether these preliminary results will be confirmed for a longer period.

Introduction

Not all patients with ulcerative colitis (UC) respond initially to treatment with biologic agents, and predicting their efficacy prior to treatment is difficult. Vedolizumab, a humanized monoclonal antibody against alpha 4 beta 7 (α4β7) integrin, suppresses immune cell migration by blocking the interaction between α4β7 integrin and mucosal addressin cell adhesion molecule 1, and is used to treat patients with UC with moderate-to-severe activity. Reports about histological features that predict vedolizumab efficacy are scarce.

Aims & Methods

We evaluated the infiltration of inflammatory cells in the colonic mucosa prior to the induction of vedolizumab and examined the association between histological features and vedolizumab efficacy.
This was a multicenter, retrospective study. Patients with UC who were treated with vedolizumab between November 2018 and April 2021 were enrolled in this study. All eligible patients had moderate-to-severe disease activity at the time of the initial treatment with vedolizumab. Biopsy specimens taken from the colonic mucosa prior to vedolizumab induction were used, and the areas positively stained for CD4, CD68, and CD45 per unit area of the lamina propria were calculated. Clinical and histological features were compared between those with and without remission at week 22, and the factors associated with clinical outcomes were identified.

Results

A total of 42 patients were included in this study. 17 (40.5%) patients achieved clinical remission at week 22. Significantly more CD4+ cells were found in the colonic mucosal tissues of patients with remission than in those without remission (odds ratio [OR]=1.44, P=0.014). In contrast, the CD68-positive area and the CD45-positive were not significantly different between the two groups. The concomitant use of corticosteroids and high Mayo scores had a negative association with the vedolizumab response (OR=0.11, P=0.008 and OR=0.50, P=0.009, respectively).

Conclusion

A high CD4+ infiltration in the colonic mucosa was associated with remission after vedolizumab treatment. Histological evaluation for CD4+ cell infiltration may be helpful in selecting patients who can benefit from vedolizumab.

Introduction

Although CADe/x systems increase colorectal polyp detection, their ability to predict histological diagnosis is limited.

Aims & Methods

The aim of this study is to determine which factors related to morphology, histology and the image characteristics are associated with histology prediction by PolyDeep, a CADe/x system.
For this analysis, 5546 still images of colorectal polyps collected in PIBAdb database (https://www.iisgaliciasur.es/home/biobanco/colorectal-polyp-image-cohort-pibadb/?lang=en) were used. The images were obtained from videos recorded by endoscopist. Each image was associated with the endoscopy description (morphology, size), the final histology diagnosis and the characteristics (size, area) related with the Red, Green and Blue model (RGB model) and the Hue, Saturation and Value model (HSV model). Finally, the Convolutional Neural Network (CNN) determined the probability a polyp was classified as neoplastic lession (adenomatous, Traditional Serrated Adenoma,TSA, Sessile Serrated Lession, SSL). We determined Polydeep classified lesions as neoplastic if the probability was ≥0.5. We performed three analysis: (1) linear multiple regression in order to determine which variables are associated with the probability of classification as neoplastic lesions. (2). A multivariate logistic regresion analysis to define the variables associated with the classification as a neoplastic lesions. (3) A multivariate logistic regression to establish which variables are associated with missclassification of polyps. We use the R software for statistical computing.

Results

PolyDeep classified 84,51% of the lesions as neoplastic lession and managed to correctly classify 85.02% of the evaluated polyps (92.8% adenomas, 82.5% TSA, 84.2% SSL and 51.6% hyperplastic). The R² in the multiple linear regression is the 0.3655. The model associated to the neoplastic diagnosis has an Akaike Information Criterion (AIC) of 3363.3 and the model associated with missclassification, has an AIC of 3547.5. The variables associated to each regression model showed in the attached table.

Conclusion

The results obtained in this study allow us to establish strategies to improve Polydeep predicted histological diagnosis.

Introduction

Limited evidence is available about predictors of response to specific medications for ulcerative colitis (UC). OCTN1, an organic cation transporter, with its variants, could modulate the inflammatory response and potentially modify drug response to immune-modulatory therapy (anti-TNFα and Vedolizumab), perhaps predicting individual response.

Aims & Methods

We first confirmed the ability of OCTN1 to differentially modulate IL1β secretion under different stimuli in a human leukemia monocytic cell line (THP-1) and in human peripheral blood mononuclear cells. We therefore prospectively enrolled a cohort of UC patients starting either anti-TNFα or Vedolizumab, determined their OCTN1 genotype and evaluated their clinical features at baseline and clinical response to therapy or disease remission (according to clinical Mayo score) after six weeks (T1) and six months (T2). We finally enrolled a cohort of UC patients in clinical and endoscopic remission (according to full Mayo score) under immune-modulatory therapy (anti-TNFα or Vedolizumab) for at least two years.

Results

OCTN1-deficient THP1 cells showed reduced IL-1β secretion in response to peptidoglycan (PGN) and Fusobacterium nucleatum (Fn), whilst primary monocytes bearing OCTN1 503F variant displayed an increased production of IL-1β in response to PGN and live bacteria. We therefore enrolled 90 patients, 50 starting anti-TNFα and 40 Vedolizumab. Patients with 503F genotype showed higher rates of pancolitis as compared to 503L genotype. Among patients with 503L phenotype, Vedolizumab results highly associated with long-term response (OR 8.92, 95%CI 0.50-11.0; p=0.019), whilst conversely co-presence of 503F genotype and Vedolizumab therapy disclosed an opposite role on the long-term response rate (OR 0.02, 95%CI 0.00-0.81; p=0.038).
The population of UC patients in clinical and endoscopic remission was composed by 92 patients, 63 under anti-TNFα and 29 under Vedolizumab. Of note, similar trends of disease extension were observed across genotypes: higher rates of pancolitis were observed in the 503F population as compared to 503L (62.5% vs 44%). Furthermore, among patients in remission with 503F genotype, the percentage of subjects receiving Vedolizumab was sensibly lower than among patients with 503L genotype (87.5% anti-TNFα vs 12.5% Vedolizumab among 503F genotype; 56% anti-TNFα vs 44% Vedolizumab among 503L genotype).

Conclusion

Mutated OCTN1 genotype (503F) favors an increased IL1β secretion from human stimulated leukocytes, thus suggesting a worse disease course with higher rate of pancolitis and lower response to Vedolizumab as compared to 503L.