Introduction

Aims & Methods

Results

Conclusion

Introduction

The prevalence of ulcerative colitis (UC) in elderly patients is rising and is associated with aging-related challenges such as functional reserve decline, compromised immune responses, and comorbidities. Anti-TNF agents and vedolizumab are effective therapies for UC but may also be associated with increased risk in elderly patients. Therefore, it is challenging to choose a first-line biologic therapy (FLBT) and data regarding FLBT for the aging population are scarce.

Aims & Methods

Our aim was to compare the safety, and persistence on drug of elderly patients with UC treated with anti-TNF agents compared to vedolizumab as first-line therapy.
Methods: This was a retrospective, single tertiary center study, including all patients with UC who initiated their FLBT at age≥60 years, between 1/1/2010 to 31/12/202. Clinical and demographic data were extracted and adverse events occurring within 52 weeks of treatment initiation were recorded.

Results

A total of 264 patients with UC aged ≥60 years were screened,62 patients were included in the final analysis [35 males (56.4%), age 68.9±7.0 years, disease duration 12.1±13.1 years]. Anti-TNF was the FLBT for 33 patients (53.2%) and vedolizumab for 29 patients (46.8%). Disease duration, gender, smoking status, concomitant exposure to steroids, concomitant use of IMM were comparable between the groups. Patients treated with an anti-TNF had a significantly lower CCI (4.9±1.86vs. 3.7±2.0, p=0.017) and more severe endoscopic disease (2.5±0.8 vs. 2.2±0.6, p=0.009) (Table 1).
Overall, at 52 weeks of follow-up, 6 patients had an adverse event. 4 patients suffered from infections:1 patient treated with Anti-TNF had severe pneumonia and needed hospitalization, 2 patients treated with vedolizumab had CMV infection and needed treatment cessation until resolution of CMV and another patient treated with vedolizumab, with known metastatic disease (CCI=10), died due to sepsis (week 17). No de-novo or recurrent malignancy were observed. One patient on vedolizumab had a skin rash treated with antihistamines and did not require treatment cessation, another patient on infliximab stopped treatment due to anaphylaxis. There were similar rates of hospitalizations between the cohorts (39.4% vs.17.2%, respectively, p=0.230). In terms of treatment persistence, median time on anti-TNF was similar to that on vedolizumab (32.00 weeks [20.00-80.57, n=13] vs 45.07 weeks [24.39-155.60, n=28] (p=0.324), respectively).

Table 1: Characteristics of study cohort

Conclusion

Anti-TNF and vedolizumab are equally safe as first-line biologic therapy among elderly patients with UC indicating that other factors may guide therapy selection in this patient population. Further prospective and larger studies are needed to fortify our findings.

Disclosure

I hereby certify that neither i and to the best of my knowledge nor anyone of the co-authors has something to disclose

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

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.

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), ulcerative colitis (UC) and Crohn’s disease (CD), is a group of chronic inflammatory disorders. Biologics are indicated for patients failing conventional maintenance therapy with moderate to severe activity. Different routes of administration, intravenous (IV), subcutaneous (SC) or oral have been approved. For chronic diseases such as IBD, some patients may prefer self-administered SC dosing to IV dosing as a less time-intensive and more convenient treatment option. This study aims to assess acceptance, safety and satisfaction of transition from IV to SC administration of Infliximab (IFX) and Vedolizumab (VDZ) in cohort of patients with IBD.

Aims & Methods

The transition from IV to SC administration was proposed to 91 patients. All patients were given two questionnaire: (a) before the switch, surveyed on the impact of the IV administration on their life and (b) 8 weeks after the switch focused on the level of satisfaction and onset of adverse event (AE). Data on medical history and treatment was collected from electronic health records.

Results

Overall, 91 patients were enrolled for switching from IV to SC therapy. All patients filled the first questionnaire. The IV therapy did not or minimally burden on patients’ life in 71% and 15 patients (16%) refused the transition. The main reasons why patients preferred to stay on IV administration were the fear of reducing follow-up visits with IBD staff and the fear of doing the therapy outside the hospital. On the other hand, 76 patients accepted and 8 weeks after the transition they completed the second questionnaire. of these 76, 39 CD and 51 male, 41 (53%) were treated with VDZ and the majority of patients (53%) were at the first line of treatment. Most of patients (67%) did not experience any difficulties in handling the device but “only” the 65% respected the correct time-table of administration. 20% of patients report at least one AE, the most common were erythema, swelling and pain in the injection site. Only the 5% should switch back to IV treament. 8 patients (10%) were switched back to IV administration due to AEs and 1 swaped to Ustekinumab.

Conclusion

In this cohort of IBD patients, we found a good acceptance rate (83.5%). The vast majority of patients (95%) was satisfied of transition from IV to SC. Moreover, we reported a good safety profile of SC therapy, AEs were mostly self-limited and local.

Introduction

Tissue factor (TF) on cell membranes initiates blood clotting upon vessel trauma and exposure of subendothelial cells to blood flow. The risk of thromboembolic events is increased in patients with ulcerative colitis (UC). Tofacitinib, a JAK1 & 3 inhibitor, recently introduced in UC therapeutics, may further increase the risk¹.

Aims & Methods

To delineate thrombosis pathophysiology in this context, TF expression in primary human colonic mesenchymal cells (PHCMC) of patients with active UC was correlated with clinical, biochemical and endoscopic data. We then treated those PHCMC with tofacitinib, with or without cytokines to better mimic the in vivo milieu they are exposed to.
PHCMC were isolated and set to ex vivo culture from endoscopic biopsies of the inflamed mucosa of 10 UC patients with an endoscopic Mayo score ≥ 2 were treated with each one of all major T helper (Th)1 (TNF-α, IFN-γ), Th2 (IL-4, IL-13) or T regulatory (Treg; TGF-β, IL-10) cytokines with or without tofacitinib. Cells were lysed, RNA was isolated and reverse-transcribed to cDNA. TF and RPL4 (housekeeping) cDNAs were quantified as C_T cycles with real-time, reverse-transcription PCR. Wilcoxon and Mann-Whitney U tests were used to compare TF ΔΔC_T for paired or unpaired values, respectively, and Spearman’s rho to correlate TF ΔΔC_T with scale clinical variables and continuous laboratory values.

Results

Increased TF mRNA abundance in PHCMC was associated with increased partial Mayo score (Spearman's rho 0.661, p < 0.044), reduced serum albumin (Spearman's rho -0.723, p < 0.05) and more severe endoscopic lesions (endoscopic Mayo score 3). No association with CRP was found (p > 0.999). Cells originating from UC patients of an endoscopic Mayo score 3 expressed 20 times more TF than those from an endoscopic Mayo score 2 (p < 0.017). Furthermore, PHCMC from difficult-to-treat patients, defined as requiring > 1 biologics, expressed 9 times more TF than those from patients requiring ≤ 1 biologics.
Interestingly, treatment of PHMC with tofacitinib did not upregulate TF. PHCMC expressed receptors and responded to treatment with all major Th1 (TNF-α, IFN-γ), Th2 (IL-4, IL-13) or Treg (TGF-β, IL-10) cytokines by further upregulating TF by 5.5-7.5 times (p 0.001 - 0.035). IL-13 had the maximal effect. Even when tofacitinib was added together with the aforementioned cytokines, it did not further upregulate TF. Instead, it tended to partially inhibit their effects; for example, it decreased upregulation of TF by IL-13 by 40%.

Conclusion

The expression of TF mRNA in active UC is significantly associated with clinically and endoscopically severe disease and resistance to treatment. Tofacitinib per se does not increase TF. Instead, it may limit the upregulating effect of pro-inflammatory cytokines.

References

1. Sandborn WJ, Panés J, Sands BE, Reinisch W, Su C, Lawendy N, Koram N, Fan H, Jones TV, Modesto I, Quirk D, Danese S. Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme. Aliment Pharmacol Ther. 2019 Nov;50(10):1068-1076.

Disclosure

Procurement of reagents and consumables for this project was partially supported by Pfizer Inc. with competitive grant # 64132481.