Abstract
Background
Patients with Inflammatory Bowel Disease (IBD), either Crohn’s Disease (CD) or Ulcerative Colitis (UC), treated with immunosuppressants and/or biotherapy might have an altered ...immune response to SARS-CoV-2 infection. The aim of this study was to evaluate the incidence of COVID-19 in a French cohort of IBD patients treated with infliximab or vedolizumab during the first epidemic wave and to identify factors associated with the risk of infection.
Methods
All patients with IBD treated with infliximab or vedolizumab from March to June 2020 in 16 French centres were included and followed for 6 months. At baseline, clinical, demographic, family and socio-professional data were collected. At each of their day hospitalization, patients reported the occurrence of symptoms of COVID-19, and the performance of a diagnostic test, if so. Serum was collected at each visit to detect immunisation by SARS-CoV-2 at the end of follow-up and to measure trough levels. Peripheral blood lymphocytes (PBLs) were frozen at each visit for 50% of patients to further analyse the immunological changes associated with COVID-19.
Results
1079 patients were included (CD n=690, mean age 41.6 years, mean disease duration 13.3 years). Clinical and demographic data at baseline are detailed in Tables 1 and 2, respectively. 143 patients (13.3%) had one or more co-morbidities associated with a risk of severe COVID-19 (hypertension 5.6%, chronic lung disease 5%, diabetes 2.4%, obesity 0.3%).
Over the 6 months of follow-up, 458 patients (42%) had active disease defined by an HBI score >4 or Mayo score >2 and/or treatment optimisation (dose increase, shortening of infusion interval, addition of an immunosuppressant or change of biotherapy). 111 patients (10.2%) received corticosteroids at least occasionally (self-medication was not excluded). 341 patients (32%) were tested for COVID-19 by nasal swab, of whom 23 were positive. Three patients were hospitalized. Regarding serology, in the first 13 centres analysed hitherto (886 patients), 20 patients were seropositive at the end of follow-up before the start of the vaccination campaign (January 2021), i.e. 2.2%, compared to 4.5% in the general population at the same period according to Santé Publique France data.
Conclusion
The preliminary analysis of this French cohort confirms that patients with IBD are not at higher risk of severe COVID-19 despite the use of biotherapy and repeated hospital stays. This population was significantly less infected than the general population. Clinical, demographic and immunological factors associated with SARS-CoV-2 infection are being analysed as well as factors associated with a lower incidence of infection compared to the general population.
Abstract
Background
In the context of the Sars-Cov2 pandemic, the management of patients with chronic diseases and/or receiving immunosuppressive drugs was of concern due to lack of data to dictate ...their management. The objectives of our study were to evaluate the characteristics and prognosis of COVID-19 among IBD patients and to study the factors associated with severe COVID-19.
Methods
We carried out a multicentre bispective study in 30 French GETAID centres. Participating centres were asked to report all consecutive COVID19 cases occurring in their IBD-cohort between March,1st and December,31st 2020. The cases had to be confirmed by a PCR test, or by a chest CT scan demonstrating COVID19 lesions. In addition to the baseline examination, patients were scheduled for a follow up visit within 3–6 months following their infection. Demographics, disease characteristics, treatments, and the clinical course of IBD were prospectively recorded. Severe COVID-19 was defined as admission to the hospital >1 day and/or use of oxygen therapy and/or death. Predictive factors for developing severe COVID-19 were explored using univariate and multivariate logistic regression.
Results
A total of 719 IBD patients with COVID 19 were included; 54.2% were women, median age was 42 years, 64.4% had Crohn’s disease (CD), and median disease duration was 10.8 years. 13.3% of the patients were active smokers;12.7% had a BMI>30. With respect to the treatment, 72(10%) patients were not on any IBD medication, 75(10.4%) were only receiving 5-ASA, 164(22.8%) received conventional immunosuppressants, and 509(70.8%) biologics.21.6% of the patients developed either diarrhoea in remitters, or an exacerbation of diarrhoea in active patients. IBD treatments were maintained unchanged, suspended or discontinued in 73.4%, 25.5%, and 1.1% of the patients. Over the follow-up period, 13.2% of the patients had a flare. A total of 68 patients developed severe COVID 19, 67(9.3%) were hospitalized for a median duration of 6 days, and 4(0.6%) patients died. In multivariate analysis, age > 50 years (OR: 2.0,CI:1.06–3.72; p=0.031), obesity (OR: 2.01,CI:1.05–4.09; p=0.037), and comorbidities (OR: 3.28,CI:1.76–6.09; p=0.0002) were factors associated with the occurrence of severe COVID 19; while immunomodulatory treatment (biologic and/or immunosuppressant) was a protective factor for developing severe COVID 19 (OR: 0.38,CI: 0.22–0.69; p=0.0012).
Conclusion
Rate of severe COVID 19 in this cohort of IBD patients was corresponding to the general population with similar risk factors for severity, i.e., age, obesity and comorbidities. Prescription of immunomodulators was protective against severe COVID 19, raising the hypothesis of their potential immunological effect on the immune storm phase of Sars-Cov2.
Abstract
Background
Neuroplastic changes in the enteric nervous system (
ENS
) observed during
IBD
might participate in physiopathological processes. Vasoactive intestinal polypeptide has been shown ...to be involved in intestinal inflammation and barrier functions. We aimed to investigate the modulation of
VIP
expression in colonic biopsies of
IBD
patient, the ability of soluble factors from biopsies to reproduce in vitro these modulations and identify soluble factors responsible.
Methods
VIP
and cytokines
mRNA
expressions were assessed in colonic biopsies of healthy subjects (
HS
) and
IBD
patients from inflamed (I) and non‐inflamed areas (
NI
). Supernatants (
SUP
) of biopsies were applied to primary culture of
ENS
and
VIP
and cytokines
mRNA
expressions were assessed. The role of cytokines in
SUP
induced changes in
VIP
expression was evaluated.
Key Results
VIP mRNA
expression was lower in biopsies of patients with Crohn's disease (
CD
) than Ulcerative Colitis (
UC
) but unchanged as compared to
HS
.
VIP mRNA
and protein expression were lower in primary culture of
ENS
incubated with
SUP
‐
CD
than with
SUP
‐
UC
. Furthermore, in
CD
but not
UC
,
SUP
‐I reduced
VIP
expression in the
ENS
as compared to
SUP
‐
NI
. Next,
IL
‐6 but not
IL
‐5,
IL
‐10,
IL
‐17,
IFN
‐γ or
TNF
‐α reduced
VIP
expression in the
ENS
. Finally, in
CD
,
SUP
‐I incubated with anti‐
IL
‐6 antibody increased
VIP
expression as compared to
SUP
‐I alone.
Conclusions & Inferences
Mucosal soluble factors from
IBD
induce
VIP
neuroplastic changes in the
ENS
.
IL
‐6 was identified as a putative soluble factor responsible in part for changes in
VIP
expression in
CD
.
Background
Colonic epithelial cells may behave as antigen‐presenting cells. Interleukin 10 (IL‐10) is known to play a major role in the intestinal immune system; however, it remains to be determined ...whether human intestinal epithelial cells express IL‐10 receptor, and whether this cytokine modulates their expression of antigen presentation‐associated molecules
Methods
The binding of biotinylated IL‐10 was studied in SW 1116, HT‐29 and T84 human colonic epithelial cell lines and freshly isolated normal colonic epithelial cells. Reverse transcription‐polymerase chain reaction was also performed to detect IL‐10 receptor mRNA. The effect of IL‐10 on antigen presentation associated molecules was assessed by flow cytometry.
Results
Biotinylated IL‐10 bound to SW 1116, HT‐29, T84, and normal colonic epithelial cells. IL‐10 receptor mRNA was detected in SW 1116 and normal epithelial cells. SW 1116 and HT‐29 cells expressed MHC class I and ICAM‐1, but not CD80, and SW 1116 constitutively expressed HLA‐DR. Interferon‐γ up‐regulated HLA‐DR and ICAM‐1 expression on both cells, whereas lipopolysaccharide increased ICAM‐1 expression only on SW 1116. IL‐10 failed to modulate these antigens, even after stimulation by lipopolysaccharide or interferon‐γ. Moreover, these molecules decreased IL‐10 binding in both lines.
Conclusion
The presence of IL‐10 receptor on intestinal epithelial cells suggest that IL‐10 may play a role in mucosal physiology, however its effect on the immune response remains to be determined.
Abstract
Background
Half of Crohn’s disease (CD) patients require surgery within 20 years of diagnosis, and post-operative recurrence (POR) is frequent. Among the risk factors of POR, the presence of ...myenteric plexitis (≥ one immune cell in contact with myenteric ganglia) at the proximal resection margin has been incorporated in the European guidelines. However, this criterion is rarely used, as little is known about the involved mechanisms. Our objectives were to determine which cells of the enteric nervous system interact with T cells and to identify the molecules responsible for these interactions.
Methods
In vivo: 29 patients (20 CD, 9 cancer) who underwent an ileocolonic resection were included. Full-thickness slices of the proximal resection margin were analysed by immunohistochemistry (IHC) to identify enteric glial cells (S100β), neurons (Hu), and T cells (CD3, CD4, CD8). T cells in contact with ganglia of the myenteric plexus were counted on each slide. In vitro: To analyse neuro-immune interactions, human enteric glial cells (EGC) were co-cultured with T cells which were activated by anti-CD3/CD28 antibodies beforehand. To determine the impact of inflammatory conditions, EGC were pre-treated with lipopolysaccharide (LPS) or IL-1β/TNFα (IT). Immunocytochemistry (ICC) was used to analyse the adhesion of T cells to EGC. The expression of adhesion molecules was determined by qPCR, western blot and ICC.
Results
IHC showed the presence of T cells, CD4+ and CD8+, in contact with EGC of myenteric ganglia in both CD and control patients. The number of T cells per ganglion was significantly higher in CD patients (5.6 ± 0.9) when compared with controls (1.2 ± 0.2) (p < 0.001), with a threshold of 1.7 T cells per ganglion, and was twice higher in CD patients suffering from POR (7.1 ± 1.4) when compared with those in whom CD did not recur (3.6 ± 0.9) (p = 0.175). POR was systematic above 7.7 T cells per ganglion. In vitro, pre-treatment of EGC with LPS and IT significantly increased the number of T cells in contact with EGC, respectively, by a factor of 2.7 (± 0.7) (p < 0.01) and 2.1 (± 0.3) (p < 0.01) when compared with the control condition. These inflammatory stimuli were associated with an overexpression of ICAM-1 in EGC as measured by qPCR, while the expression of MAdCAM and NCAM was not increased. This up-regulation of ICAM-1 was confirmed at the protein level.
Conclusions
Our results indicate that T cells interact with EGC in vitro and in vivo. These interactions are increased under inflammatory conditions and are associated with an up-regulation of ICAM-1. This suggests a role of EGC in the formation of plexitis, possibly through the binding of LFA-1 to ICAM-1. Further experiments will be carried out to confirm this possibility.
Abstract
Background
Despite the availability of new drugs in IBD, there is still a high unmet medical need for patients suffering from ulcerative colitis. ABX464 has potent anti-inflammatory ...properties impacting the expression of miR124 as shown in HIV studies. We performed a first-in-disease Phase 2a study with ABX464 in patients with moderate-to-severe ulcerative colitis intolerant and/or refractory to existing treatments.
Methods
The study was performed in 15 European centres. A total of 32 patients were randomised (2:1) to ABX464 50 mg QD orally or placebo for 8 weeks. The primary endpoint was safety of ABX464 and key secondary endpoints included remission (assessed a rectal bleeding sub-score = 0 and an Endoscopy sub-score ≤1 and at least one-point decrease in stool frequency sub-score from baseline to achieve a stool frequency sub-score ≤1), endoscopic improvement (Mayo endoscopic score of 0 or 1), and clinical response and histological healing. Centrally-read endoscopy with histopathology were performed at Day 0 and Day 56. After the blinded induction phase, patients had the option to roll over into a 52-week open-label 50 mg QD ABX464 study.
Results
Total of 29 (90.6%) patients (20 randomised to ABX464 and 9 to placebo) completed the induction study. Baseline demographics and characteristics showed well-balanced groups. The overall safety profile of ABX464 was overall very good with no serious adverse events (SAE). Safety profile was similar to the one seen in the clinical development in the HIV reservoir reduction indication. Main efficacy results are presented below.
ABX464 (n = 20)
Placebo (n = 9)
p value
Clinical remission
35%
11%
0.16
Endoscopic improvement
50%
11%
0.03
Clinical response
70%
33%
0.06
Total Mayo score reduction
−53%
−27%
0.03
Partial Mayo score reduction
−62%
−32%
0.02
Faecal calprotectin decrease >50%
75%
50%
miRNA124-fold expression
7.69
1.46
0.004
ABX464-101 study endpoints results at Day 56.
The interim data from the 52-week maintenance study show further improvement of Partial Mayo Score and reduction in faecal calprotectin.
Twenty-two patients were included in the 52 weeks maintenance study. The interim analysis with a mean maintenance treatment duration of 5.1 months (max: 9.0 months; min: 3.5 months) showed further improvement in both Partial Mayo score and faecal calprotectin levels.
Conclusions
In this Phase 2a study in patients with moderate-to-severe UC, ABX464 50 mg QD orally for 8 weeks was safe and well tolerated. Clinical, endoscopy, histopathology, and biomarker analysis all changed in a consistent way and all in favour of ABX464. These data support a Phase 2b multi-centre placebo-controlled dose-ranging study in UC and a Phase 2a study in Crohn’s disease.
Abstract
Background
Inflammatory bowel diseases (IBD) are disabling disorders. The IBD-Disability Index (IBD-DI) was developed for quantifying disability in IBD patients but is difficult to use. The ...IBD-Disk is a shortened and visual adaptation of the IBD-DI. It has not been validated yet. The main objectives were to validate the IBD-Disk in a large cohort of IBD patients and to assess its variability over time.
Methods
From March 2018 to July 2019, IBD patients from three university-affiliated hospitals responded twice to both IBD-Disk and IBD-DI at 3–12 months intervals (NCT03590639). Validation included concurrent validity, reproducibility, internal consistency, and evaluation of IBD-Disk correlation with IBD activity. Variability was assessed by comparing scores between baseline and follow-up visits.
Results
A total of 559 patients (73% Crohn’s disease, 27% ulcerative colitis) were included and 389 were followed up (Table 1). There was a good correlation between IBD-Disk and IBD-DI scores (r = 0.75, p < 0.001) (Figure 1). The IBD-Disk was significantly higher in patients with active disease according to Physician/Patient Global Assessment (Figure 2), clinical scores (Figure 3), and biomarkers levels, compared with patients with inactive disease. Reproducibility was excellent (intra-class correlation coefficient = 0.90), as well as internal consistency (Cronbach’s α = 0.89). The IBD-Disk score significantly decreased in patients becoming inactive over time.
Table 1.
Clinical characteristics of the study population (n = 559).
Gender, n (%)
Female
313 (56)
Age at baseline, mean (SD)
40.1 (14.1)
Age at diagnosis, mean (SD)
28.1 (12.5)
Disease location (CD / UC), n (%)
L1 / E1
114 (28) / 32 (22)
L2 / E2
103 (25) / 52 (35)
L3 / E3
187 (46) / 62 (42)
L4 / Pouchitis
38 (9) / 3 (2)
Disease behaviour in CD, n (%)
B1
219 (54)
B2
130 (32)
B3
58 (14)
Perineal location in CD, n (%)
Never
295 (72)
Past
84 (21)
Active
28 (7)
Extra-intestinal manifestation, n (%)
123 (22)
Intestinal resection, n (%)
172 (31)
Stoma, n (%)
25 (4)
Perianal surgery, n (%)
85 (15)
Seton, n (%)
7 (1)
Figure 1.
Correlation between total scores of IBD-Disk and IBD-DI at baseline (n = 418).
Figure 2.
Distribution of IBD-Disk scores at baseline according to (A) Patient Global Assessment (n = 513), (B) Physician Global Assessment (n = 514).
Figure 3.
Distribution of IBD-Disk scores at baseline according to (A) HBI score (CD), (B) Mayo sub-score (UC).
Conclusion
This is the first study to validate the IBD-Disk in a large cohort of IBD patients, demonstrating that it is a valid and reliable tool for quantifying disability in clinical practice. Further studies are warranted to assess its correlation with endoscopic activity, to explore its responsiveness to change, and to evaluate the factors associated with disability.
Background: Tumour necrosis factor (TNF) plays a key role in the pathogenesis of Crohn disease (CD). RDP58 is a novel anti-inflammatory decapeptide which was developed using a novel rational design ...strategy. Recently, RDP58 has proved to be a potent inhibitor of TNF production at a post-transcriptional step. The aims of this study were to investigate the anti-inflammatory properties of RDP58 ex vivo in human CD and in vivo in an experimental model colitis. Methods: Biopsies and lamina propria mononuclear cells from inflamed colonic mucosa of 18 CD patients were cultured for 24 h in the presence or absence of RDP58. TNF was quantified in a bioassay; interferon (IFN)-γ and interleukin (IL)-1 levels were measured by enzyme-linked immunosorbent assays. Colitis was induced by intra-rectal administration of 2, 4, 6 trinitrobenzene sulphonic acid (TNBS) in rats. Inflammation was assessed following 7 days of oral therapy with RDP58 or vehicle alone. Results: RDP58 led to decreased TNF and IFN-γ (but not IL-1 ) production by biopsies and lamina propria mononuclear cells from CD patients. In rats with TNBS-induced colitis, oral RDP58 therapy reduced weight loss and diarrhoea and improved macroscopic and histological inflammation scores. Conclusions: Our results suggest that RDP58 may be an effective therapy for CD with the clinical advantage of an oral administration.
Rho proteins are involved in the regulation of several cellular functions. Data from in vitro studies suggest that RhoA could be involved in the inflammatory response. We investigated the role of ...RhoA and its downstream effector Rho kinase in intestinal inflammation.
Activation of RhoA was assessed by pull-down assays. A specific inhibitor of Rho kinase, Y-27632, was used to examine the role of Rho kinase in inflammatory response in vivo and in vitro by molecular biology and by immunological and biochemical approaches.
Increased activation of RhoA was found in inflamed intestinal mucosa of patients with Crohn’s disease and of rats with 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Oral administration of Y-27632 in rats significantly reduced the colonic inflammation. In vitro, activation of RhoA alone was sufficient to induce tumor necrosis factor production. Y-27632 inhibited production of tumor necrosis factor-α and interleukin-1β by lamina propria and peripheral blood mononuclear cells. Rho kinase inhibition prevented nuclear factor κB activation and I-κB phosphorylation and degradation. We showed that Rho kinase associates with and activates I-κB kinase α and that Y-27632 prevents I-κB kinase activation.
Our study provides the first evidence that Rho kinase activates I-κB kinase and, thus, nuclear factor κB, suggesting a key role of Rho kinase in inflammatory responses and intestinal inflammation. Specific inhibition of Rho kinase may be a promising approach for the treatment of patients with Crohn’s disease.
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