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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.