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

Crohn's disease (CD) location would influence the risk of complications and therapeutic strategies. The objective of this study was to compare the clinical presentation at diagnosis and the natural history of colonic CD in comparison to ileal CD and ulcerative colitis (UC) in pediatric-onset IBD.

Aims & Methods

All children (< 17 years) with a diagnosis of CD or UC made between 1988 and 2011 in a population-based registry were followed retrospectively until 2013. The presentation at diagnosis, the risks of complications, surgery, hospitalization and exposure to different treatments in ileal CD (L1), colonic CD (L2) and UC were compared. Disease location was defined at diagnosis. In case of extension of the disease (L1 or L2 to L3), follow-up was censored.

Results

A total of 215 L1 patients, 234 L2 patients and 337 UC patients were included. At diagnosis, the proportion of male (L1 53.5%; L2 53.4%; UC 42.7%; p=0.012), age at diagnosis (15.0; 13.7; 14.0 years; p=0.003), family history of IBD (12.6%; 12.7%; 5.0%; p=0.005), diagnostic delay (3.0; 3.0; 2.0 months; p=0.001) and smoking prevalence (11.6%; 8.1%; 5.6%; p=0.041) were different between the three groups. Over the study period, incidence of L1, L2 and UC were 0.65 [0.57-0.74], 0.71 [0.62-0.81] and 1.02 [0.92-1.14] per 100,000 person-years, respectively. Bloody stool and diarrhea at diagnosis was observed in 14.9% respectively; 44.4%; and 91.1% (p < 0.001) and 47.0%; 71.8%; and 65.0% (p < 0.001) of L1, L2 and UC. At diagnosis, granuloma was identified in 12.6% of L1 patients and 31.2% of L2 patients (p<0.001). The risk of extension to L3 was significantly higher in the L2 group than in the L1 group (at 5 years - 37% vs. 14%, p<0.001). L2 location was associated with a lower risk of luminal fistula (HR 0.41 [0.21-0.79], p=0.008) but a higher risk of anoperineal lesion (HR 2.11 [1.29-3.45], p=0.003). The prevalence of extra-intestinal manifestations, articular (p<0.001) and cutaneous (p<0.001) was higher in L2 CD. While the risk of surgery was significantly higher in case of L1 location (at 5 years - 37%, 13% and 13%; p<0.001), the risk of hospitalization (at 5 years - 22%, 39% and 33%; p=0.01), exposure to corticosteroids (at 5 years - 55%, 69% and 67%; p<0.001), immunosuppressants (at 5 years - 47%, 61% and 42% - p<0.001) and anti-TNF (at 5 years - 16%, 35% and 22%; p<0.001) were higher in case of L2 location.

Conclusion

The clinical presentation and evolution of ileal and colonic CD at diagnosis differ significantly. Colonic location is associated with a high risk of perianal CD, extra-intestinal manifestations, hospitalization and exposure to steroids, immunosuppressants and anti-TNFs. These differences could justify different therapeutic approaches in the future.

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

Subcutaneous (SC) Infliximab (IFX) is non-inferior to intravenous (IV) IFX, for maintenance of remission in inflammatory bowel disease (IBD) (1). There are limited data on factors affecting the decisions of patients who choose SC administration of biologics (2, 3). Our centre offered suitable patients SC IFX from November 2022.

Aims & Methods

(1) Determine disease-related, economic, social and personal factors that affect the decision of a patient with IBD to transition from IV to SC administration of IFX.
(2) Assess effects of SC administration on pharmacokinetics and disease control. Participants completed a questionnaire on their IBD history, personal and financial circumstances, and reasons for electing or declining to transition. Clinical and biochemical data were retrieved from the electronic patient record (EPR). A bivariable logistic regression model was used to determine factors associated with electing to transition.

Results

144 patients were offered the opportunity to transition during the study period. 80 (55.5%) agreed to transition, 64 (44.5%) declined. 101 patients (70.1%) agreed to participate in the study. 59.4% were male, 67.3% had Crohn’s disease. Age ranged was 18-82 (median 41) years. Infusion frequency was every 4 (9.8%), 6 (22.8%), 7 (2.0%), or 8 weeks (65.4%). 76% were employed/self-employed, 41.6% had a medical card and 44.6% had private health insurance. Median (IQR) travel time was 90 mins (40, 130). 48 patients (47.5%) reported that they missed school/work for their infusions. At baseline, median (IQR) laboratory results were CRP 1.2mg/L (0.6, 2.7), IFX trough 7.4mg/mL (4.9, 11.8), faecal calprotectin 39 mg/g (10, 98), IBD-Control 14 (13, 16). 8 weeks after first SC dose, median (IQR) results (n=36) were CRP 1.1mg/L (0.8, 2.0) IFX trough 17.8mg/mL (12.5, 21.4), IBD-Control 16 (14, 16). The strongest reasons to transition (% agree/ strongly agree on five-point Likert) were, “I want to transition because it will…”
(1) reduce my travel time (94.5%),
(2) fit my work/life balance better (87.3%) and
(3) reduce my time away from work/school (74.5%). The strongest reasons against transition were,
(1)I would miss having my bloods checked regularly (84.8%),
(2) I feel safer attending the infusion unit (80.4%),
(3) I would not be able to voice concerns about my treatment as easily (80.4%) and
(4) I would miss regular contact with a healthcare professional (69.6%). Table 1 shows results of binary logistic regression used to determine factors associated with the likelihood of electing to transition.

Conclusion

SC IFX is safe, effective and well-tolerated by those who choose to transition. It is attractive to many patients, because attending for IV infusions can interrupt their employment, education and family life, but cost is a significant barrier for some patients. IBD teams must be adequately resourced to assure patients who transition that they will continue to have ready access to high-quality medical care and disease monitoring. Discrepancies in healthcare markets may provide a perverse incentive to continue receiving IV biologic, for those who would prefer SC.

References

1. Schreiber S, Ben-Horin S, Leszczyszyn J, Dudkowiak R, Lahat A, Gawdis-Wojnarska B, et al. Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease. Gastroenterology. 2021;160(7):2340-53.
2. Remy C, Caron B, Gouynou C, Haghnejad V, Jeanbert E, Netter P, et al. Inflammatory Bowel Disease Patients’ Acceptance for Switching from Intravenous Infliximab or Vedolizumab to Subcutaneous Formulation: The Nancy Experience. Journal of Clinical Medicine. 2022;11(24):7296.
3. Ventress E, Young D, Rahmany S, Harris C, Bettey M, Smith T, et al. Transitioning from Intravenous to Subcutaneous Vedolizumab in Patients with Inflammatory Bowel Disease [TRAVELESS]. Journal of Crohn's and Colitis. 2022;16(6):911-21.

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

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Histological outcomes and the immune landscape were assessed in an UC patient cohort at baseline and after 8 weeks tofacitinib.

Aims & Methods

In this prospective study, 40 patients with moderate to severely active UC received tofacitinib 10 mg twice daily for 8 weeks. Clinical, endoscopic and histological outcomes were assessed at baseline and week 8 and colon biopsies were stained for JAK1-3, Tyrosine kinase 2 (TYK2) and Signal transducer and activator of transcription (STAT) 1-6 total protein expression using immunohistochemistry (IHC). Histological remission was defined as a Robarts Histopathology Index (RHI) ≤3 points without mucosal neutrophils and histological response as 50% decrease in RHI compared to baseline. Response was defined as histological remission and endoscopic Mayo score (EMS) ≤1 (histo-endoscopic mucosal improvement). Biopsies were scored by a blinded pathologist. Whole slide images with multiple biopsies per patients were stained using IHC, analyzed using automated cell detection (QuPath) and quantified in percentages by dividing the number of positive stained cells by the total number of cells on the slide. Outcomes were compared between responders and non-responders (NR).

Results

Out of 40 patients, 26 (65%) had severe endoscopic disease (EMS 3) with a median RHI of 14. Thirty-one patients (78%) had failed prior anti-Tumor Necrosis Factor (anti-TNF) agents and 18 (55%) failed vedolizumab. At week 8, 23 patients (58%) achieved histological remission, 34 (85%) histological response and 15 (38%) histo-endoscopic mucosal improvement. A significant decline in RHI compared to baseline was observed after 8 weeks both in responders (14 vs 0, p<0.001) and NR (15 vs 6, p=0.002). In the entire cohort, total STAT1 (p<0.001), STAT3 (p=0.002) and STAT5 (p=0.026) expression significantly decreased after 8 weeks treatment compared to baseline, which was not different between responders and NR (Table). However, responders to tofacitinib expressed significantly lower total STAT1 levels compared to NR at 8 weeks (p<0.001). Likewise, JAK2 (p=0.008) and total STAT2 expression (p=0.004) were significantly lower in responders compared to NR at 8 weeks, although no significant decrease compared to baseline was observed. A trend towards lower baseline JAK1, JAK2 and total STAT4 expression and higher total STAT6 expression was seen in responders compared to NR.

Conclusion

Tofacitinib resulted in histological response in the majority of UC patients and led to a substantial decline of total STAT1, STAT3 and STAT5 expression both in responders and NR. Yet, after 8 weeks significantly lower total STAT1 levels were observed in responders compared to NR. Responders tended to express lower JAK1, JAK2 and total STAT4 and higher total STAT6 levels at baseline.

Disclosure

This study was funded and supported by Pfizer.

Introduction

Cobitolimod (MW 5925.18 Da) is a DNA-based oligonucleotide functioning as an immunomodulatory Toll-like receptor 9 agonist. Cobitolimod is in phase III clinical development as a new therapy for moderate to severe left-sided ulcerative colitis (UC). This phase Ib study aimed to evaluate the pharmacokinetics (PK), safety and tolerability of rectally administered cobitolimod in patients with moderate to severe UC.

Aims & Methods

The phase Ib open-label study was conducted at a single center in Sweden (NCT05404074). The patients had moderate to severe UC defined by a 3-component Mayo score of 5 to 9, with an Investigator read endoscopic subscore ≥2, and with stool frequency and rectal bleeding subscores each ≥1. Patients received one cobitolimod enema (500 mg/50 ml) at week 0, and blood samples for PK analysis were collected pre-dose, 15 min, 30 min, 1h, 2h, 4h, 8h, 12h and 24h after dosing. Patients received a second cobitolimod enema (500 mg/50 ml) at week 3, and at week 6 the degree of clinical remission was evaluated. Clinical remission was defined by the 3-component Mayo score with a rectal bleeding subscore = 0, a stool frequency subscore ≤1 (≥1 point decrease from baseline), and an Investigator read endoscopic subscore ≤1. Patients in clinical remission at week 6 received a third cobitolimod enema (500 mg/50 ml), and blood samples were collected for a second PK analysis as described above. The primary endpoint was PK parameters: maximum plasma concentration (C_max), time to C_max (T_max), area under the curve from 0 to timepoint t (AUC_t) and half-life (T_1/2). Secondary endpoints included safety and tolerability.

Results

Eight patients with active disease were enrolled in the study and included in the safety analysis set. One patient was excluded from the pharmacokinetic analysis set (PKAS) due to an immediate bowel movement following administration. Of the 7 patients included in the PKAS, 4 patients achieved clinical remission at week 6. Rectal administration of 500 mg cobitolimod at week 0 resulted in median C_max of 21.7 ng/ml, median T_max of 1h, median T_last of 4h, and median AUC_0-last of 71.7 h*ng/ml (n=7). For the 4 patients in remission at week 6, corresponding numbers were: median C_max of 15.5 ng/ml, median T_max of 0.5h, median T_last of 4h and median AUC_0-last of 27.6 h*ng/ml. T_1/2 was <2.5h both at week 0 and week 6.
In total, 24 adverse events occurred in the study, out of which the majority was mild and judged as unlikely related to study drug. No serious adverse events were reported.

Table 1. PK parameters per patient

Conclusion

The study demonstrates that rectally administered cobitolimod results in a low systemic exposure of short duration both in patients with active disease and in clinical remission. Cobitolimod was safe and well tolerated at a dose of 500 mg.

Disclosure

Thomas Knittel is a consultant for and a shareholder in InDex Pharmaceuticals, Sweden. Pernilla Sandwall is a former employee and a shareholder in InDex Pharmaceuticals, Sweden. Christine Dieterich Johansson is employed by InDex Pharmaceuticals, Sweden. Arezou Zargari is employed by and a shareholder in InDex Pharmaceuticals, Sweden. Johan Bring is a consultant for InDex Pharmaceuticals, Sweden. Per Hellström receives consultancy fees from: Clinical trial consultants, Sweden; ROSE pharma, USA; Pharmanovia, Denmark; Swedish Agricultural University, Uppsala; Pharmacosmos, Denmark; Stockholm Diabetes Association, Sweden; Celltrion, Finland; Mag-tarmförbundet, Sweden; Karolinska Institutet, Sweden; Bristol-Myers Squibb, Sweden; ClinSmart, Sweden; InDex Pharmaceuticals, Sweden; Takeda pharmaceutical company; Mediahuset, Sweden; Bonnier Healthcare Sweden; Folkuniversitetet, Stockholm, Sweden; Biogaia, Stockholm, Sweden; Norgine, Denmark; Nanologica AB, Södertälje, Sweden.