Introduction

Acute infusion-related reactions (IRRs) are common adverse events associated with infliximab, affecting up to 23% of patients. Their etiology involves cytokine release, complement activation, and mast cell degranulation. Consequently, individuals with a history of immunological hypersensitivity reactions are often perceived to be at high risk due to their exaggerated immune responses, and are frequently prescribed premedication.

Aims & Methods

We aimed to determine if patients with immunological hypersensitivity background, receiving infliximab for inflammatory bowel disease (IBD), have an increased risk of IRRs. This retrospective cohort study included all patients diagnosed with IBD who underwent intravenous (IV) infliximab at our centre over a 13-year period. All patients received standard infliximab 2-hour infusion protocol, preceded by premedication with 200mg of IV hydrocortisone. IRRs were defined as any type of mild to severe reaction occurring during infusion or within 2 hours of its completion. Patients were considered to have an allergic predisposition if they had atopic diathesis (such as allergic rhinitis, asthma or atopic dermatitis) or a documented history of allergy to other medications.

Results

Ninety-five patients, with a mean age of 35 ± 13 years at the initiation of infliximab therapy, were included in the study, with females accounting for 52.6%. The majority of patients were diagnosed with Crohn’s disease (n=76, 80%), while the remaining 19 patients (20%) had ulcerative colitis. A history of allergy was reported in 20 patients (21.1%) within the cohort.
Over the study period, a total of 258 person-years (PY) of exposure to infliximab were recorded, with a median of 12 infusions per patient (interquartile range: 5-33). In most cases, infliximab therapy was combined with immunomodulators (n=63, 66.3%).
Fourteen IRRs occurred during the follow-up period, resulting in an overall incidence rate of 49.5 per 1000 PY. Patients with and without a history of immunological hypersensitivity showed comparable incidence rates of IRRs (32.5 per 1000 PY and 57.8 per 1000 PY, respectively), as well as similar cumulative incidence (15% and 22.7%, respectively). No statistically significant difference was observed between the two groups (p=0.446).

Conclusion

Having an immunological hypersensitivity background does not appear to increase the risk of developing acute infliximab infusion-related reactions. Consequently, it does not warrant specific premedication or additional precautionary measures.

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

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

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

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

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.