Clinical features and biomarker research advances in immunoglobulin 4-related digestive system disorders

Table 2 Translational integration of diagnostic modalities across prevalent clinical scenarios

Prevalent clinical scenario	Prioritized sequence of diagnostic tests	Expected interpretations & decision logic	Evidence level & basis
Indeterminate pancreatic mass	Imaging: CT/MRI	Imaging: Look for “sausage-like” enlargement, capsule-like rim	High (imaging, IgG4, EUS-FNB limitations: Based on ICDC & large multicenter cohorts). Moderate (Tph, plasmablasts: Requires broader validation)
	Serology: Serum IgG4, IgG2	Serology: IgG4 > 2 × ULN. Normal IgG4 does not rule out AIP (beware of the prozone effect)
	Cellular markers: Plasmablasts, Tph cells. Targeted biopsy: EUS-FNA/FNB	Cellular: Highly expanded plasmablasts/Tph cells support IgG4-RD
		Biopsy: Storiform fibrosis and lymphoplasmacytic infiltrate; standard EUS-FNA may miss focal fibrosis
Isolated biliary stricture	Imaging: MRCP/ERCP	Imaging: Long, continuous, symmetrical strictures (lower CBD)	High (imaging, cytology limitations: Supported by current consensus guidelines). Moderate (IgG2, plasmablasts)
	Serology: Serum IgG4, IgG2	Serology: Elevated IgG4 and IgG2 (> 5.3 g/L)
	Cellular markers: Plasmablasts	Cellular: Plasmablasts elevated independent of serum IgG4
	Targeted biopsy: Endobiliary brush cytology/forceps biopsy	Biopsy: Primary utility is ruling out cholangiocarcinoma. High false-negative rate for IgG4-SC as superficial brushings often miss deep-seated storiform fibrosis
Suspected relapse	Imaging: PET-CT/MRI	Imaging: Detects early subclinical organ recurrence	Moderate (plasmablasts & Tph predictive value; longitudinal cohorts). Low/exploratory (eotaxin-3, TARC)
	Serology: Eotaxin-3, TARC, IgG4	Serology: Eotaxin-3 identifies high-relapse lymphadenopathy phenotype; TARC evaluates systemic burden
	Cellular markers: Plasmablasts, Tph cells	Cellular: Significant rise in Plasmablasts/Tph cells before clinical or biochemical (LFTs) worsening
	Targeted biopsy: Usually deferred unless new atypical lesions appear	Biopsy: N/A
Fibrotic/“burnt-out” disease	Imaging: CT/MRI	Imaging: Persistent residual fibrotic masses/strictures without active swelling	Moderate (IFN-α/IL-33 axis response). Low (HE4: Based on exploratory translational studies)
	Serology: HE4, IFN-α/IL-33 axis	Serology: HE4 elevated (marker of established fibrosis); IFN-α/IL-33 low (no active inflammation)
	Cellular markers: Plasmablasts	Cellular: Normal or decreased post-therapy
	Targeted biopsy: Deep core biopsy (if needed)	Biopsy: Dense storiform fibrosis with sparse plasma cells. Logic: Differentiate residual scarring from active disease to prevent unnecessary prolonged steroid exposure

CT: Computed tomography; MRI: Magnetic resonance imaging; EUS-FNA/FNB: Endoscopic ultrasound-guided fine-needle aspiration/fine-needle biopsy; ICDC: International Consensus Diagnostic Criteria; Tph: Peripheral helper T cells; MRCP: Magnetic resonance cholangiopancreatography; ERCP: Endoscopic retrograde cholangiopancreatography; IgG4: Immunoglobulin G4; ULN: Upper limit of normal; AIP: Autoimmune pancreatitis; IgG4-RD: Immunoglobulin G4-related disease; TARC: Thymus and activation-regulated chemokine; IgG4-SC: Immunoglobulin G4-related sclerosing cholangitis; PET: Positron emission tomography; N/A: Not applicable; IFN: Interferon; IL: Interleukin; HE4: Human epididymis protein 4; LFTs: Liver function tests; CBD: Common bile duct.