Introduction

Few population-based studies have investigated the long-term surgery rates of Crohn’s disease (CD). The present study is a continuation of the Veszprem IBD population based cohort with a follow-up since 1977.

Aims & Methods

Our aim was to analyze the long-term disease course and surgery rates over different therapeutic eras in a prospective population-based database from Veszprem Province, including incident CD patients. Patient inclusion was between January 1, 1977 and December 31, 2018; follow-up ended December 31, 2020. Both in-hospital and outpatient records were collected and comprehensively reviewed at diagnosis and during clinical follow-up. Immunomodulators became widespread in Hungary from the mid-1990s, while biological therapies have been covered by the National Health Insurance Fund since 2008. Surgery rates were examined in three different eras based on time of diagnosis: cohort-A, 1977-1995; cohort-B, 1996-2008; and cohort-C, 2009-2018.

Results

Data of 946 incident CD patients were analyzed (male/female: 496/450; median age at diagnosis:28 years(y) [IQR: 22-40]), with a median of 15y(IQR 9-21) follow-up. Overall immunosuppressive therapy use was increasing by time (48.0%/62.4%/65.5%), as well as the probability of biological therapy initiation within 5 years of diagnosis (0.0±0%/7.3±1.2%/22.7±2.2%) in cohorts A/B/C. The probability of disease behavior progression from luminal (B1) disease to stenosing or penetrating phenotype (B2/B3) was significantly decreasing (27.1±SD5.3%/ 21.5±2.5%/11.3±2.2% in cohorts A/B/C after 5 years [pLogRank<0.001]). The probability of first resective surgery between cohorts A/B/C were 33.3±3.8%/26.5±2.1%/28.1±2.4% after 5 years; 46.1±4.1%/32.6±2.2%/33.0±2.7% after 10 years; and 59.1±4.0%/41.4±2.6% (cohorts A/B) after 20 years. There was a significant decrease in surgery risk between cohorts A and B [pLog Rank=0.002]. Surgery risk remained similar between cohorts B and C [pLog Rank=0.665]. The cumulative probability of re-resection in cohorts A/B/C was also decreasing (17.3±4.1%/12.6±2.6%/4.7±2.0% after 5 years [pLog Rank=0.001]). A cox-regression multivariate analysis showed that stenosing or penetrating disease (B2/B3) behavior (HR 4.52; 95%CI 3.60-5.68; p<0.001) and ileal (L1) location at diagnosis (HR 1.30; 95%CI 1.05-1.61; p=0.016) were independent predictors of resective surgery.Table 1.

Table 1. Predictive factors for first resective surgery in incident CD patients diagnosed between 1977 and 2018 – Cox-regression analysis

Conclusion

We report a gradual decline in reoperation rates and disease behavior progression in CD over time with the lowest values in the biological era. In contrast, there was no further decrease in the probability of first major resective surgery after the immunosuppressive era.

Introduction

Microscopic colitis (MC) has been associated to various autoimmune diseases. Previous studies on the association between MC and psoriasis have focused on psoriasis as a risk factor for MC. Data from large scale cohort studies investigating the risk of future psoriasis in MC, however, are lacking.

Aims & Methods

We aimed to examine the association between MC and psoriasis by conducting a nationwide, population-based, matched cohort study in Sweden from 2007-2021. In total, we identified 8,404 patients with biopsy-verified MC (diagnosed in 2007-2017), 37,303 matched reference individuals, and 8,381 siblings without MC. Information on MC was obtained through the ESPRESSO cohort (a histopathology database containing data on all gastrointestinal biopsies in Sweden from 1965-2017). Data on incident psoriasis was gathered from the National Patient Register. Using Cox regression, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

During a median follow-up of 9.2 years (interquartile range=6.7-11.7), 179 MC patients and 440 reference individuals were diagnosed with psoriasis (241 vs 131 events per 100,000 person-years), corresponding to one extra case of psoriasis in 91 patients with MC followed for 10 years. After adjustment for the matching variables (birth year, sex, county of residence and calendar period) and level of education – as a proxy for socioeconomic status - we computed an aHR of 1.82 (95%CI=1.53-2.17). Stratifying by sex, estimates were similar and when examining the aHR across different lengths of follow-up, we found significantly elevated estimates up to 10 years after MC diagnosis. Compared to MC-free siblings, the aHR was 1.85 (95%CI=1.36-2.51).

Conclusion

Patients with MC are at an almost doubled risk of being diagnosed with psoriasis compared to the general population. Our findings suggest clinicians should consider psoriasis in MC patients with skin lesions.

Disclosure

Dr. Ludvigsson coordinates a study on behalf of the Swedish IBD quality register (SWIBREG). That study has received funding from the Janssen corporation. Dr Ludvigsson has also received financial support from MSD to develop a paper reviewing national healthcare registers in China. Dr. Ebrahimi has served as an advisory board member for Boehringer Ingelheim. AS has received consultancy fees from ICON plc, Abbvie, Novarits, and Eli Lilly. AS has received lecture fees from Janssen Cilag and UCB.

Clinical Case Summary

Crohn’s disease (CD) is a multi-factorial immune-mediated inflammatory condition of the gastrointestinal tract (GIT). While CD-related granulomas typically occur within the GIT, they can appear in other areas such as lymph nodes, mesentery, peritoneum, liver, and lungs. This case highlights a rare instance of renal granuloma secondary to CD and discusses an effective treatment approach. An 18-year-old male presented to a GP with a one-year history of abdominal pain. There was no significant medical or family history. Physical examination was unremarkable. Laboratory findings showed raised white cell count, elevated erythrocyte sediment rate, and renal dysfunction. He was referred to a nephrologist who noted additional symptoms of diarrhoea and occasional per-rectal bleeding with no significant improvement in symptoms or renal function after complete cessation of non-steroidal anti-inflammatory drugs. Renal biopsy confirmed acute interstitial nephritis and granuloma, therefore he was referred to a gastroenterologist to rule out CD or sarcoid. Colonoscopy showed pancolitis with rectal sparing and segmental biopsies revealed chronic colitis with granulomas confirming CD. Fecal calprotectin was raised. Further investigations ruled out autoimmune disease, tuberculosis and sarcoidosis as causes for renal impairment. Treatment involved steroid tapering followed by intravenous infliximab induction and maintenance therapy with subcutaneous injections fortnightly. Renal function and GIT symptoms improved with infliximab monotherapy, though dose escalation to weekly infliximab injections was required at seven months due to loss of response from subcutaneous infliximab. At one year, colonoscopy showed endoscopic remission, with ongoing improvement in renal function (creatinine 194 to 111 umol/L) and resolution of pyuria. In conclusion, we present a rare case of CD-associated interstitial nephritis, showing a positive clinical response to infliximab monotherapy.

References

1. Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68:s1-s106.
2. Eade MN, Cooke WT, Williams JA. Liver disease in Crohn's disease. Scand J Gastroenterol. 1971;6:199-204.
3. Whitehead R. Pathology of Crohn's disease. In: Kirsner JB, Shorter RG, eds. Inflammatory bowel disease. 2nd ed. Philadelphia: Lean and Febiger; 1980:296-310.

Disclosure

Nil

Introduction

The disease course of ileal and ileocolonic Crohn’s disease (CD) is highly heterogeneous, and continuous objective measures of disease activity are needed. Intestinal Ultrasound (IUS) is a non-invasive modality assessing disease activity in IBD. The International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) is an index for grading CD activity. However, importance of the ultrasonic findings in the terminal ileum (TI) at diagnosis and the responsiveness of ultrasonic findings to different treatments is still limited. We thus aimed to investigate the IUS characteristics of the TI at diagnosis and changes in IUS parameters in response to treatment 3 months after inclusion.

Aims & Methods

Patients with new-onset IBD are recruited in the ongoing multicentre prospective inception cohort study, the IBD Prognosis Study. IUS is performed at diagnosis and after three months (3M). IBUS-SAS (0-100) is scored for the TI and incorporates the bowel wall thickness (BWT), bowel wall stratification (BWS), colour Doppler signal (CDS), and inflammatory fat (I-FAT). Only patients with ileal and ileocolonic CD who had an available IBUS-SAS of the TI at diagnosis were included. Patient without subsequent assessment at 3M were excluded (except resected patients). Transmural remission was defined as IBUS-SAS < 12 (corresponding to BWT < 3 mm and no signs of inflammation). If the operator assessed the TI as complete transmural remission at 3M without providing numeric BWT values, the IBUS-SAS was set to 8. Patients treated with corticosteroids for > 72 hours or with any IBD treatment > two weeks prior to baseline IUS were excluded from analysis.

Results

Baseline IBUS-SAS at TI was available in 46 CD patients (ileal: 21, ileocolonic: 25). According to the Montreal classification, 31 patients had B1 (non-stricturing, non-penetrating disease), 9 patients had B2 (stricturing disease), and 6 patients had B3 (penetrating disease).
Among all patients, the mean IBUS-SAS was 60.7 at diagnosis vs. 33.7 at 3M (p<0.001). Mean baseline BWT decreased from 5.8 to 4.6 (p=0.011) at 3M. The other IBUS-SAS parameters also had significant reductions (p=0.021, p=0.001, and p<0.001 for BWS, CDS, and I-FAT, respectively). After three months, 12/39 (30.8%) of non-resected patients were in transmural remission.
Changes in IBUS-SAS between diagnosis and 3M stratified by initiated treatment are presented in Figure 1 (​https://ibb.co/mBcVF9b​​​). In total, 6 (13.0%) patients started only systemic steroids with a mean IBUS-SAS reduction of 20.6 (p=0.025), 5 (10.9%) patients started systemic steroids + biological therapy with a mean reduction in IBUS-SAS of 37.6 (p=0.022), 11 (23.9%) patients started on systemic steroids + immunomodulator with a mean reduction in IBUS-SAS of 35.6 (p<0.001), 4 (8.7%) patients started on immunomodulator + biological therapy with a mean reduction in IBUS-SAS of 24.8 (p=0.271), and 9 (19.6%) patients were started on budesonide with a mean reduction in IBUS-SAS of 9.4 (p=0.287). Finally, 4 (8.7%) patients did not commence on any treatment and these patients increased their IBUS-SAS by 6.75 (p=0.536), and 7 (15.2%) patients were resected as primary treatment with 1, 2, and 4 having the B1, B2, and B3 Montreal classification, respectively. Baseline IBUS-SAS was significantly higher for patients undergoing resection than patients without resection, (87.9 vs. 55.8, P<0.001).

Conclusion

IUS performed at diagnosis and after three months can effectively identify patients achieving ultrasonic response and / or transmural healing to multiple drug classes. All four IBUS-SAS activity parameters demonstrated responsiveness to treatment and patients without treatment increased their IBUS-SAS non-significantly. Transmural remission was achieved in up to 30 % of non-resected patients within 3M.

Introduction

Therapeutic progress in inflammatory bowel disease (IBD) is limited by the lack of understanding of the pathophysiology and the mechanisms involved in response or lack/loss of response to treatments. IBD patients are treated with anti-inflammatory drugs, including biologics such as anti-tumor necrosis factor (TNF) agents, which have been crucial in achieving steroid-free remission and prevention of long-term complications. However, a significant subgroup of patients becomes refractory to these biologicals due to the development of immunogenicity, characterized by the presence of anti-drug antibodies (ADAs). The antibody production and peripheral tolerance are initiated and maintained within lymphoid organs, such as the peripheral lymph nodes, but the exact role of immune cells in these lymphoid structures and whether they are involved in anti-drug antibody (ADA) formation is unknown.

Aims & Methods

We aimed to unravel the pathophysiology behind the development of anti-drug antibodies. Therefore, we performed ultrasound-guided inguinal lymph node needle biopsies from which we isolated leukocytes along with PBMCs from the same patients. Leukocyte populations were analyzed at single cell level via high dimensional phenotyping through mass cytometry (CyTOF).

Results

Using this unique approach, we have so far results from 4 Crohn’s Disease (CD) patients with ADAs (75% females, 50% active disease) and 4 without ADAs (50% females, 75% active disease). Active disease was defined, as an observation of an elevated CRP (c-reactive protein) (>5 mg/L) and/or calprotectin >250 (mg/kg), including symptoms (Harvey-Bradshaw index score > 4 or disease activity index score-CDAI >150).
The proportion of CD4⁺ TEMRA (terminally differentiated effector memory T-cells), CD4⁺ effector and central memory T-cells were increased in the peripheral lymph nodes of patients that developed immunogenicity. Mature NK cells, classical and non-classical monocytes were also increased. Furthermore, the levels of the alpha-4 integrin expression were higher in the lymph node T-lymphocytes, as well as, in the lymph node naïve and memory B-cell subsets in the patient group with ADAs.

Table: Cytometry and Biochemical Characteristics.

Conclusion

Lymph node T-helper cells, monocytes and NK cells potentially play a role in the development ADAs in IBD patients treated with biologics. Although, there was no significant difference in the proportion of naïve and memory B-cells, our findings concerning the alpha-4 integrin expression levels also indicate that both lymph node T and B-lymphocytes, are possibly characterized by a higher migratory potential during immunogenicity conditions.

References

1. Stein RE, Lee DY, Leonard MB, et al. The association between drug levels, anti-drug antibodies, and therapeutic response during infliximab therapy in pediatric Crohn’s disease. J Crohns Colitis 2014; 8: S434.
2. Bodini G, Savarino V, Dulbecco P, et al. The influence of anti-adalimumab antibodies on adalimumab trough levels, TNF-alpha levels and clinical outcome. J Crohns Colitis 2014; 8: S42
3. Stefan S, Sandborn WJ, Choi J, et al. Anti-drug antibodies separate responses of markers of inflammation (c-reactive protein, fecal calprotectin) in Crohn’s disease patients treated with certolizumab pegol. Inflamm Bowel Dis 2014; 20: S68.
4. Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs. 2017;31(4):299-316. doi:10.1007/s40259-017-0231-8.
5. Brun MK, Goll GL, Jørgensen KK, et al. Risk factors for anti-drug antibody formation to infliximab: Secondary analyses of a randomised controlled trial. J Intern Med. 2022;292(3):477-491. doi:10.1111/joim.13495.

Disclosure

The authors state no conflict of interest.

Introduction

Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that includes ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases are different but show an uncontrolled intestinal immune response that generates tissue inflammation. Dendritic cells (DC) are phagocytic professional antigen presenting cells that link the innate and adaptive immune systems. Indeed, they are the only cell type able to stimulate naïve T cells generating an antigen-specific immune response. In humans, DC can be divided into plasmacytoid (pDC) and c conventional type 1 and 2 (cDC1, cDC2). Although cDC migration towards the GI mucosa is enhanced in IBD, the mechanisms underlying these migrations and whether biological drugs can modulate them are currently unknown.

Aims & Methods

This study aimed to analyze DC migratory capacity towards the GI mucosa, and whether biological drugs with different mechanisms of action can modulate this process in health and IBD.This is a cross-sectional observational postmarketing study where the modulatory effect of different biological treatments on samples from patients with an endoscopic diagnosis of IBD and healthy controls was studied ex vivo. Peripheral blood mononuclear cells (PBMC) were obtained from 15 patients per group and were cultured in presence of golimumab or ustekinumab. Following culture, surface markers expression was determined, assessing the differential effect of biological drugs (if any) over the DC subsets in the different groups. After that, the migratory capacity of circulating DC towards CCL2, CCL25, and MadCam1 from the different study groups was determined. Finally, we evaluated the DC migratory capacities in presence of biological drugs or with culture media alone.

Results

The cDC2 subset showed higher expression levels of β7 and CCR5 compared to cDC1. Golimumab and ustekinumab did not modify the expression of the homing markers in any studied subset in pDC and cDC2.On the contrary, in cDC1 both golimumab and ustekinumab increased CCR6 expression in qCD patients and CCR9 in aUC patients. Regarding to the migratory capacities of the different DC subsets toward intestinal chemoattractants ustekinumab decreased the migratory capacity of cDC2 from CD patients towards a medium supplemented with MadCam1 and increases toward CCL2 in case of cDC1 from CU. In the case of migratory capacities of cDC2 from HC were increased by ustekinumab and golimumab toward CCL2 and CCL25 just in case of golimumab.

Conclusion

cDC2 showed more migratory profile markers than other DC populations. Golimumab and ustekinumab modify the expression of the homing markers just in cDC1 subset. Nevertheless, ustekinumab and golimumab modify the migratory capacities of cDC in IBD patients and HC, but do not exert any effect on pDC. These effects occur in a different manner in CD and UC indicates that the behavior of cDC is different in CD and UC, and that the migration capacity of this subset is not dependent exclusively on homing markers.

Introduction

Inflammatory Bowel Diseases (IBD) are chronic inflammatory disorders characterised by alterations of acute relapses and remission. The past decades have brought substantial advances in the pharmacological management of IBD by the introduction of immunosuppressive agents, biologics and lately small molecules. Although, the sustained efficacy of the currently available anti-inflammatory therapies is still far from optimal. Therefore, the development of novel therapies represents a major unmet clinical need in this field. Recently the enrichment of the coagulation pathway genes and among these, plasminogen activator inhibitor 1 (PAI-1) was described in IBD, whereas PAI-1 emerged as a link between the epithelium and inflammation. Moreover, the genetic deletion of PAI-1 impaired the severity of experimental colitis in mice.

Aims & Methods

Based on these, our aim was to develop and test novel PAI-1 inhibitors for the treatment of IBD. Novel, peptide-based PAI-1 inhibitors were designed and screened in silico, then the selected ones were synthetized using the ixPeptide® platform. The inhibitory potential of the peptides was determined by an in vitro PAI-1 activity assay. Cytotoxicity was monitored in vitro in Hela cells with the CellTiter Glo assay. Based on the in vitro results LDN-071 was selected for further analysis. Experimental colitis was induced in mice with 3% DSS and after the induction of colitis 10 mg/bwkg LDN-071 was administrated per os for four consecutive days. The changes of body weight, spleen weight and colon length were measured. Haematoxylin eosin (HE) and Periodic acid-Schiff (PAS) staining were performed for histology. ELISA and qRT-PCR measurements were applied to analyse the mucosal cytokine expressions. In vivo toxicity of LDN-071 was determined in mice.

Results

LDN-071 significantly inhibited PAI-1 in vitro without decreasing the cell viability in a concentration range of 1µM-1mM. The administration of 10 mg/bwkg LDN-071 in the DSS-treated mice prevented the body weight loss, the development of bloody diarrhoea, the decrease of colon length and increase of the spleen weight, which were displayed by the DSS+vehicle-treated animals. The histological analysis of the colon revealed that DSS treatment induced a severe transmural inflammation, ulceration, loss of crypt structures and goblet cell depletion. Importantly, all of these parameters were significantly impaired by the administration of 10 mg/bwkg LDN-071. Additionally, mucosal gene and protein expressions of TNF-α, IL-1β and IL-6 were significantly impaired by PAI-1 inhibition. Importantly, no signs of toxicity were LDN-071 observed in mice exposed to 100 mg/bwkg LDN-071 for 7 days.

Conclusion

Our results showed that LDN-071, a novel peptide-based inhibitor of PAI-1. It significantly reduces the severity of experimental colitis in mice. We propose that the inhibition of PAI-1 could be a potential novel therapeutic strategy in IBD.

Disclosure

LDN-071 PAI-1 inhibitor is owned by Ladon Therapeutics Ltd.