Introduction

Anti-TNF drugs are highly effective for treating Inflammatory Bowel Disease (IBD) but have a high chance of loss of response, particularly due to immunogenicity. Using immunomodulators (IMM) can partly overcome this. The HLA-DQA105 polymorphism was identified as a predictor of anti-infliximab antibodies (AIA). However, the impact of this polymorphism in real-world studies and its association with other factors related to the development of immunogenicity needs to be established.

Aims & Methods

We aim to study the association of the polymorphism HLA-DQA1*05 with the development of AIA in a real-life cohort of patients with IBD. We conducted a retrospective cohort study including adult patients with Crohn's Disease (CD) and Ulcerative Colitis (UC) who were or have been taking infliximab (IFX) with a minimum follow-up of 6 months. DNA amplification and sequencing by Sanger methodology were used to identify the presence of the HLA-DQA1*05 polymorphism. The presence of AIA was evaluated through ELISA, and IFX trough levels (IFX TL) were assessed by a point-of-care methodology. A Cox regression analysis was performed to assess the impact of the polymorphism on the time until the development of AIA and its association with other relevant factors (use of concomitant IMM, body mass index, gender, IFX TL, baseline albumin and type of disease - CD vs UC).

Results

We included 115 patients (76% CD and 24% UC) of whom 60% were male with a median age at diagnosis of 30 years old (IQR 20-42). Almost half of the patients (52%) started combination therapy with IMM. Thirty patients (26%) developed AIA, with no significant difference between patients with CD and UC (23% vs 36%, p=0.2). The median time until the development of AIA was 8 (IQR 5-16) months. During follow-up, 34% had a primary or secondary loss of response; 37% stopped IFX and 21% had adverse effects. The prevalence of the polymorphism was 70.4%. Among patients who developed AIA, there was no difference between HLA-DQA1*05 carriers and non-carriers (21% vs 38%, p=0.06). However, there was a significant difference in the concomitant use of IMM, which was lower in the group of patients who developed AIA (13% vs 40%, p<0.01). Half of the patients needed to optimize IFX dosing and there were no differences among polymorphism carriers and non-carriers (48% vs 53%p=0.6). Patients who developed AIA had significantly lower median IFX TL when compared to patients without AIA (0.4, IQR 0.35-1.4 vs 7.4, IQR 3.4-13.5, p<0.001). There was no difference in the median IFX TL according to the presence of the polymorphism (p=0.8). The risk of developing AIA was similar between HLA-DQA1*05 carriers and non-carriers (HR 0.8, 95%CI 0.4-1.6, p=0.4) even after adjusting for the other risk factors associated with immunogenicity (HR 0.5, 95%CI 0.1-1.9, p=0.3). No differences were found according to the type of disease. Patients with the HLA-DQA1*05 polymorphism and who were using a concomitant IMM had the lowest risk of developing AIA, which was significantly lower when compared to patients who carried the polymorphism and were not taking the IMM (HR 0.2, 95%CI 0.04-0.9, p=0.03).

Conclusion

In this Portuguese cohort of IBD patients, the HLA-DQA105 polymorphism was highly prevalent and did not influence the development of AIA. Further real-world studies with larger sample sizes are needed to determine the utility of this polymorphism as a predictor of AIA.

References

1) Sazonovs A et al. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn’s Disease. Gastroenterology, 2019;
2) Fuentes-Valenzuela E et al. Influence of HLADQA1*05 Genotype in Adults With Inflammatory Bowel Disease and Anti-TNF Treatment With Proactive Therapeutic Drug Monitoring: A Retrospective Cohort Study. Inflammatory Bowel Diseases, 2023

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is frequently indicated in patients who underwent Roux-en-Y gastric bypass (RYGB) surgery. (1, 2) However, due to the altered anatomy, it is challenging to gain pancreatobiliary access in patients following a RYGB. Several strategies are currently available, but all have their disadvantages. Laparoscopy-assisted ERCP (LA-ERCP), the current golden standard, has higher success rates but also comes with logistical challenges of intraoperative ERCP, peri-operative complications and high costs. (3 - 5) Endoscopic ultrasound directed ERCP (EDGE) is a technique used to create a gastro-gastrostomy by placing a lumen apposing metal stent (LAMS) between the gastric pouch and the excluded stomach, facilitating subsequent ERCP.(6) Although EDGE gained more popularity over the last few years, prospective studies are lacking.

Aims & Methods

The aim of this study is to provide prospective evidence for the efficacy and safety of EDGE, including fistula closure.This multicentre prospective cohort study included all consecutive patients scheduled for elective ERCP after RYGB surgery. EDGE was performed as a two-step procedure. Primary endpoint was overall technical success. Secondary endpoints were technical success of LAMS placement and ERCP individually, persistent fistula and other procedure-related adverse events (AEs).

Results

Between January 2021 and August 2024, 26 patients were included in 4 Dutch hospitals. Overall technical success was achieved in 25/26 patients (96.2%). Median LAMS indwelling time was 14 days [IQR 11 – 28 days]. Two EDGE-related AEs occurred (7.7%); one perforation of the contralateral duodenal wall following scope insertion and one bleeding after LAMS placement. Two ERCP-related AEs occurred (7.7%): one CBD perforation and one post-ERCP pancreatitis. Two patients were lost to follow-up. None of the remaining patients had a persistent fistula, based on radiologic or endoscopic evidence (0/24). No mortality occurred.

Conclusion

This prospective study shows that two-step EDGE is relatively safe and associated with high technical success, without any cases of a persistent fistula. However, AEs occurred in 4 patients (15.4%), of which two were EDGE-related (7.7%).

References

1. Yang H, Petersen GM, Roth MP, Schoenfield LJ. Risk factors for gallstone formation during rapid loss of weight. Digestive diseases and sciences. 1992;37(6):912-8.
2. Haal S, Guman MSS, Boerlage TCC, Acherman YIZ, de Brauw LM, Bruin S, et al. Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery (UPGRADE): a multicentre, double-blind, randomised, placebo-controlled superiority trial. Lancet Gastroenterol Hepatol. 2021;6(12):993-1001.
3. Gangwani MK, Aziz M, Haghbin H, Iqbal A, Dillard J, Dahiya DS, et al. Comparing EUS-directed Transgastric ERCP (EDGE) Versus Laparoscopic-Assisted ERCP Versus Enteroscopic ERCP: A Network Meta-analysis. J Clin Gastroenterol. 2024;58(2):110-9.
4. da Ponte-Neto AM, Bernardo WM, de ACLM, Josino IR, Brunaldi VO, Moura DTH, et al. Comparison between Enteroscopy-Based and Laparoscopy-Assisted ERCP for Accessing the Biliary Tree in Patients with Roux-en-Y Gastric Bypass: Systematic Review and Meta-analysis. Obes Surg. 2018;28(12):4064-76.
5. Abbas AM, Strong AT, Diehl DL, Brauer BC, Lee IH, Burbridge R, et al. Multicenter evaluation of the clinical utility of laparoscopy-assisted ERCP in patients with Roux-en-Y gastric bypass. Gastrointestinal endoscopy. 2018;87(4):1031-9.
6. van Wanrooij RLJ, Bronswijk M, Kunda R, Everett SM, Lakhtakia S, Rimbas M, et al. Therapeutic endoscopic ultrasound: European Society of Gastrointestinal Endoscopy (ESGE) Technical Review. Endoscopy. 2022;54(3):310-32.

Clinical Case Summary

A 71-year-old female presented to the gastroenterology clinic following a two year history of dysphagia and sensation of food sticking in the oesophagus. Her dysphagia was limited to solid foods, and symptoms were not exacerbated by positional change. Pain was mostly localised around the sternal notch where she would have the sensation of a food bolus. Over the preceding 2 years, she had experienced about 7.5kg of weight loss with no constitutional symptoms of fevers or fatigue. Her past medical history included hypertension, dyslipidaemia, lower back pain, cold agglutinin disease, monoclonal B lymphocytosis and peripheral arterial disease. On examination, there were no signs of malnourishment or palpable lymph nodes in the axilla, neck or supraclavicular region. Her abdomen was soft and non-tender. Given largely non-illuminating blood results, an oesophageal-gastroduedonoscopy was performed. However, no findings were noted, specifically no oesophageal webs, Zenker diverticulum, gastroparesis, trachealisation of the oesophagus or corrosive pathology. H. pylori was also not isolated on histopathology. A barium swallow was then performed which showed extensive external compression of the proximal third of the oesophagus at the level of the arch of the aorta, most indicative of dysphagia lusoria (Fig 1). Computed tomography angiography (CTA) showed retroesophageal aberrant right subclavian artery bifurcating from the ascending aorta independent of a brachiocephalic artery and causing external oesophageal compression (Fig 2 & 3). Given this definitive diagnosis, the patient was then seen in clinic where management of dysphagia lusoria was explained. Despite ongoing symptoms, the patient decided to continue with conservative management and lifestyle modifications, which included eating smaller bites and increase in fluid intake. Although an extensive compression typically requires surgical intervention, our patient was stable at two-year follow-up (Fig 4 A-B).

References

Figure 1: Barium swallow examination showing extrinsic compression of the proximal third of the oesophagus at the level of the aortic arch (white arrow).
Figure 2: Axial view of computed tomography angiography (CTA) showing the posterior course of the retroesophageal aberrant right subclavian artery.
Figure 3: Axial view of computed tomography angiography (CTA) showing compression of oesophagus (white arrow) by the retroesophageal aberrant right subclavian artery (white arrowhead).
Figure 4: Computed tomography angiography (CTA) multi-planar reconstruction (MPR) showing the posterior course of the right subclavian artery (white arrow), crossing the mediastinum and compressing the oesophagus. A. coronal view B. Sagittal view

Disclosure

None.

Clinical Case Summary

An 18-year-old female was diagnosed with very early-onset Crohn’s disease (CD) in 2008. Due to steroid dependence, adalimumab 40 mg biweekly was initiated in 2019, with escalation to 40 mg weekly in February 2023 following secondary loss of response. In November 2023, despite clinical and biochemical remission (CRP <0.5 mg/L, fecal calprotectin <50 µg/g), the patient developed painful purpuric and ulcerated lesions on both lower limbs. Histological examination of a skin biopsy confirmed leukocytoclastic vasculitis (LCV), revealing perivascular neutrophilic infiltrates, nuclear debris, and fibrinoid necrosis in post-capillary venules. Infectious and autoimmune screening, including ANA, antiphospholipid antibodies, p-ANCA, and c-ANCA, were negative. Following consultation with an immunologist, adalimumab was discontinued, and oral prednisone 25 mg/day was initiated. However, the clinical course was complicated by a skin abscess, which was treated with oral amoxicillin/clavulanate (1 g three times daily for 3 days). As vasculitic lesions worsened, the patient was hospitalized, and prednisone was increased to 50 mg/day. Intravenous cefazolin (2 g every 8 hours for 5 days) was also administered, resulting in stabilization and partial clinical improvement. A multidisciplinary team, including a gastroenterologist, immunologist, and dermatologist, opted to initiate off-label treatment with upadacitinib 30 mg/day, a selective Janus kinase 1 (JAK1) inhibitor. After four weeks, the patient showed improvement in the vasculitic lesions, and corticosteroid therapy was tapered. At the six-month follow-up, the patient remained on upadacitinib monotherapy, with sustained clinical and biochemical remission of both CD and LCV, without any adverse events. This case highlights the potential of JAK1 inhibition as an effective and safe therapeutic option for leukocytoclastic vasculitis in patients with Crohn’s disease.

References

Photographic documentation of the clinical case:
1. Images showing the initial presentation of petechial and purpuric lesions on the lower limbs.
2. Images of severe vasculitis characterized by confluent and ulcerated lesions.
3. Images documenting cutaneous healing following upadacitinib treatment.