Introduction

Upper endoscopy (EGD) with esophageal biopsies is required to rule out eosinophilic esophagitis (EoE) in patients reporting dysphagia. Moreover, EoE monitoring currently requires esophageal biopsies to assess treatment response based on eosinophil counts on histology. Non-invasive screening and monitoring strategies are needed to reduce the diagnostic delay and streamline the follow-up of patients with EoE.

Aims & Methods

In this prospective cross-sectional multicenter study conducted at three EoE-referral centers in Italy, we investigated whether absolute eosinophil count (AEC) and eosinophil percentage (EosPercent) could a) predict a diagnosis of EoE among patients referred for dysphagia, b) serve as a marker of histological remission in treated EoE patients. We enrolled consecutive patients undergoing EGD with six esophageal biopsies for suspected or known EoE. For all patients, a full blood count was obtained prior to the EGD. A diagnosis of active EoE or histological remission was performed based on current guidelines. Non-EoE dysphagia (NED) patients were identified based on the presence of <15 eosinophils/high-power field in all six esophageal biopsies while off eosinophil-depleting treatments. Demographic, clinical, AEC, and EosPercent data were collected. Kruskal-Wallis Rank Sum Test and Pearson’s Chi-squared were used for comparisons as appropriate. ROC curve analysis was used to assess the diagnostic accuracy (AUC) of AEC and EosPercent. Significance threshold was p<0.05.

Results

Of the 92 included patients, 33 had active EoE, 18 had EoE in histological remission while on budesonide orodispersible tablets (BOT) or proton pump inhibitors (PPI), and 41 had NED. Patients with EoE were younger and more frequently male and atopic compared to NED (p<0.01 for all). Overall, 98% (50/51) of EoE had AEC, and 84.3% (43/51) had EosPercent within the normal range. Similarly, 100% (41/41) of NED had AEC, and 90.2% (37/41) had EosPercent within the normal range. There were no differences between EoE and NED in terms of proportion of patients with AEC or EosPercent above the upper limit of normal (p>0.4 for all) (Table 1). Median AEC [380 (210, 460)/mm3 vs 120 (70, 220)/mm3; p<0.001) and EosPercent [5.40 (3.60, 7.05)% vs 1.80 (0.8, 3.0)%; p<0.01] were significantly higher in active EoE compared to NED. Based on ROC curve analysis, a cut-off of 155 eosinophils/mm3 segregated active EoE from NED with AUC of 0.82, specificity of 91.0%, and sensitivity of 65.8%, while a cut off value of 2.5% of EosPercent had AUC of 0.83 with 68.2% specificity and 93.5% sensitivity for the identification of EoE among patients with dysphagia. In terms of prediction of BOT or PPI response, median AEC [380 (210, 460)/mm3 vs 150 (98, 268)/mm3; p<0.01) and EosPercent [5.40 (3.60, 7.05)% vs 1.85 (1.55, 4.47)%; p<0.01] were significantly higher in active EoE compared to EoE in histological remission. Based on ROC curve analysis, a cut-off of 375 eosinophils/mm3 had AUC of 0.75 with 94.1% specificity and 54.5% sensitivity, while a cut off value of 2.25% of EosPercent had AUC of 0.79 with 93.5% specificity and 60.0% sensitivity for the identification of histological remission among EoE patients (Table 2).

Conclusion

AEC and EosPercent are within the normal range in most EoE patients regardless of histological disease activity. Nevertheless, AEC and EosPercent values accurately predict a diagnosis of EoE among patients reporting dysphagia, as well as histological remission among BOT- or PPI-treated EoE patients. If these findings are replicated on a larger scale, AEC and EosPercent could be used as biomarkers in clinical practice.

Table 1) Circulating eosinophil	EoE, n=51	NED, n=41	p value
AEC within normal range	50/51 (98%)	41/41 (100%)	0.72
Eos Percent within normal range	43/51 (84.3%)	37/41 (90.2%)	0.41
Table 2) Biomarker	AUC	Specificity	Sensitivity
AEC in the diagnosis / monitoring of response in EoE	0.82 / 0.75	91% / 94.1%	65.8% / 54.5%
EosPercent in the diagnosis / monitoring of response in EoE	0.83 /0.79	68.2% / 93.5%	93.5% / 60.0%

Introduction

Recent evidence supports diagnosing coeliac disease without biopsy in patients with significantly elevated tissue transglutaminase (IgA-tTG) antibodies. However, the implementation of this no-biopsy approach relies on accurate and consistent serological testing across laboratories. In this nationwide survey, we aimed to evaluate the availability and variability of coeliac disease testing across the United Kingdom.

Aims & Methods

We conducted a cross-sectional telephone survey of biomedical scientists and laboratory managers from NHS trusts and health boards across England, Wales, Scotland, and Northern Ireland. Data collected included assay types, reporting methods, upper limit of normal (ULN) thresholds, turnaround times, total IgA testing, the availability of anti-endomysial antibodies (EMA),

Results

A total of 356 sites were approached, with a 96% response rate (n=342). Of responding sites, 177 performed coeliac serology tests in-house, while 165 transferred samples externally. Among sites performing tests, 12 different tTG assays were identified, with considerable variability in ULN thresholds ranging from 3 to 30 IU/mL, even within laboratories using the same assays. The median turnaround time for IgA-tTG results was 7 days (range 1–21 days). Only 43% of laboratories routinely measured total IgA when IgA-tTG was requested. EMA testing was available in 83% of laboratories.

Conclusion

Significant variability exists in coeliac serology testing across UK laboratories which poses a challenge for the implementation of the no-biopsy approach in clinical practice. Efforts to standardise serological testing are urgently needed. Until such standardisation is achieved, local assay validation remains critical.

Disclosure

MGS and HAP received speaker fees from Thermo Fisher.

Introduction

Type 1 AIP is the most common presentation of IgG4-related disease. Serum IgG4 levels are widely used in initial screening and diagnosis, with levels ≥135 mg/dL recommended as part of the diagnostic criteria. However, its diagnostic specificity is limited as it can be elevated in a broad spectrum of neoplastic, infectious, and autoimmune diseases. Histological diagnosis though definitive, remains challenging in real life clinical practice. In recent years, IgG4/IgG ratio has been proposed as a promising alternative serum biomarker.

Aims & Methods

We aimed to study the diagnostic utility of serum IgG4/IgG ratio compared to serum IgG4 alone in the diagnosis of Type 1 AIP. We identified a cohort of patients from 2015 to 2021 who had raised serum IgG4 levels in Tan Tock Seng Hospital, Singapore. Associations between serum IgG4 level and IgG4/IgG ratio were compared to confirmed AIP diagnosis and characteristic computed tomography (CT) and magnetic resonance imaging (MRI) features (diffuse pancreatic swelling, rim-like enhancement). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated at IgG4/IgG thresholds of ≥15% and ≥20%.

Results

Our sample included a total of 60 patients with raised serum IgG4 levels. 21 patients had been diagnosed with Type 1 AIP, and 39 patients had not.
The majority of our patients had serum IgG4 ≥135 mg/dL (n=53, 88.3%). However, there was no significant association between the conventional serum IgG4 cut off of ≥135 mg/dL and the diagnosis of AIP (p = 0.687). In contrast, serum IgG4/IgG ratio demonstrated significantly higher values in patients with AIP compared to those without (median 23.2% vs 13.9%; p < 0.001). Analysis by logistic regression of IgG4/IgG ratio showed an acceptable performance with an area under the curve of 0.779, sensitivity of 92.3%, and specificity of 52.4%.

Variable	Type 1 AIP Present (n=21)	Type 1 AIP Absent (n=39)	Test Statistic	p-value
IgG4/IgG ratio	23.2 (24.0 ± 14.2)	13.9 (13.4 ± 4.5)	U = 184	<0.001
Serum IgG4 ≥135 mg/dL	18/21 (85.7%)	35/39 (89.7%)	Fisher's exact	0.687

We performed further analysis to determine a threshold for diagnostic utility of serum IgG4/IgG ratio. A ratio of ≥20% was strongly associated with AIP diagnosis (OR = 13.2, 95% CI: 3.08–56.5; p < 0.001), with high specificity (92.3%) and PPV (78.6%). Reducing the diagnostic threshold to ≥15% increased sensitivity to 76.2% (vs 52.4% at ≥20%) and improved NPV 84.4%, however this reduced specificity to 69.2%.

Subset analysis was performed among patients with Type 1 AIP (n=21) to evaluate for relationship between serum biomarkers and typical imaging findings (diffuse pancreatic swelling, rim-like enhancement). When stratified to a cut off of ≥135 mg/dL, the association between serum IgG4 levels with imaging findings trended towards positivity, but was not statistically significant (OR 3.14, p = 0.0553, φ 0.196). The IgG4/IgG ratio demonstrated a stronger association with typical imaging findings, although still not achieving statistical significance (OR = 1.065, p = 0.129). This subset analysis is likely limited by the small sample size.

Conclusion

This study demonstrates that serum IgG4/IgG ratio is a superior serological marker compared to serum IgG4 alone, particularly in the diagnosis of type 1 AIP. A threshold ratio of ≥20% demonstrated strong association with AIP diagnosis, with high specificity and PPV.
Our findings support the incorporation of IgG4/IgG ratio - particularly at a cut-off of 20% - as a valuable adjunct in diagnosis of suspected type 1 AIP, and we recommend further research in a larger cohort to validate this data.

References

1. Wallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Arthritis Rheumatol. 2020;72(1):7–19.
2. Umehara H, Okazaki K, Kawa S, Takahashi H, Yoshino T, Matsui S, et al. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-related disease. Mod Rheumatol. 2021;31(3):529–33.
3. Lanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4-related disease. BMJ. 2020;369:m1067.
4. Uchida K, Okazaki K. Current status of type 1 (IgG4-related) autoimmune pancreatitis. J Gastroenterol. 2022;57(10):695–708.
5. Xia CS, Zhang S, Duan L, Zhao CW, Zhang F. Diagnostic performances of serum IgG4 concentration and IgG4/IgG ratio in IgG4-related disease. Clin Rheumatol. 2017;36(11):2769–74.

Introduction

An increasing number of patients in clinical practice are transitioning from intravenous (IV) to subcutaneous (SC) dosing of infliximab. In this simulation study, we evaluated hypothetical dosing scenarios for both (normal to obese) adults and children switching from steady-state IV to SC infliximab, as well as those initiating SC infliximab therapy.

Aims & Methods

By combining two previous published infliximab models (1,2) we were able to simulate both IV and SC dosing in adults and children. Various dosing regimens were simulated using a large virtual population. In each scenario, the distribution of trough concentrations and area under the plasma concentration time curve (AUC) was calculated.

Results

Peak levels were higher after IV dosing compared to SC dosing, while trough levels were higher after SC dosing leading to more stable infliximab levels over time. Overall exposure remained largely similar when switching from a standard IV to SC dosing regimen. Patients with a high body mass index and those on high-frequency IV dosing regimens of infliximab demonstrated reduced exposure when transitioned to the fixed SC dose. Paediatric patients exhibited higher exposure on the fixed SC dose. Simulation of SC induction schemes demonstrated early achievement of steady state plasma levels.

Conclusion

Infliximab exposure (AUC) remains largely similar when transitioning from standard IV to SC dosing. Current dosing regimens may not be optimal for morbidly obese patients, paediatric patients and patients on high-frequency infliximab regimens. These findings provide a foundation for future clinical research to refine SC infliximab dosing in these populations.

References

1) Hanzel J, Bukkems LH, Gecse KB, D’Haens GR, Mathôt RAA. Population pharmacokinetics of subcutaneous infliximab CT-P13 in Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther. 2021;54:1309–19.
2) Fasanmade AA, Adedokun OJ, Blank M, Zhou H, Davis HM. Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn’s Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials. Clin Ther. 2011;33:946–64.

Disclosure

RW has no conflicts of interest. RK is an employee and stockholder of Insight RX, a company developing clinical decision software. LD has served as a speaker for AbbVie, Celltrion, Janssen-Cilag and Takeda and has developed continuing education materials for Ferring, all outside the submitted work.