IgG4-Related Disease (IgG4-RD): A Comprehensive Review

1. Overview and Definition

2. Classification Criteria

2019 ACR/EULAR Classification Criteria for IgG4-RD

Step 1 - Entry Criteria (Yes/No)

Step 2 - Exclusion Criteria (any one present = excluded)

Step 3 - Inclusion Weighted Scoring System

Classification threshold: Score ≥20 = IgG4-RD

3. Etiopathogenesis

3.1 The IgG4 Molecule Itself

• Weak binding to C1q and Fc-γ receptors (CH2 domain differences) - poor complement activation
• Low participation in antibody-dependent cell-mediated cytotoxicity
• Unique ability to undergo "Fab arm exchange" - forming bispecific "half-antibodies" incapable of cross-linking antigens and forming immune complexes
• IgG4 deposition in kidneys suggests possible immune complex injury in some organs, but this is not the dominant mechanism

3.2 CD4+ Cytotoxic T Lymphocytes (CTLs) - Central Effectors

• Secrete perforin, granzyme A and B - directly injure target tissues
• Release IFN-γ, IL-1β, TGF-β1 - activate macrophages and fibroblasts
• Drive the profibrotic response by activating myofibroblasts
• Are found concentrated at sites of disease in tissue biopsies
• Decline after B cell depletion (confirming B cell-CTL interaction)

3.3 B Cells and Plasmablasts

• Markedly expanded plasmablast populations circulate in active disease (useful biomarker)
• B cells act as antigen-presenting cells to CD4+ CTLs via MHC class II
• A specific subset of T follicular helper (Tfh) cells drives IgG4 class switching in germinal centers
• Multiple self-antigens have been identified that drive B cell expansion (e.g., laminin-511, prohibitin, galectin-3, annexin A11, HSP70 in specific organ manifestations)
• Depletion of B cells (rituximab, inebilizumab) produces rapid, robust clinical responses

3.4 Macrophages and Fibroblasts

• Activated macrophages (M2 polarization) and activated myofibroblasts amplify TGF-β1-driven fibrosis
• B cell depletion reduces infiltrating activated myofibroblasts, thereby decreasing fibrosis

3.5 Th2 Skewing and Atopy

• Peripheral eosinophilia and elevated serum IgE (sometimes >10× ULN) are common
• These are partially independent of pre-existing atopy - IgG4-RD itself contributes to eosinophilia/IgE elevation
• Circulating Th2 memory cells found only in patients with pre-existing atopy histories

3.6 Genetic Factors

• HLA associations (HLA-DRB1 alleles) have been reported, particularly in Japanese populations with autoimmune pancreatitis
• No single causative autoantigen or gene has been definitively identified

4. Clinical Features and Organ Presentations

4.1 General Features

• Insidious onset, often without systemic symptoms (fever, weight loss are uncommon - their presence should prompt exclusion)
• Organs swell progressively, mimicking malignancy or infection
• Most patients are middle-aged to elderly men
• Multiple-organ involvement in 60-70% at diagnosis

4.2 Proliferative vs. Fibrotic Phenotypes

4.3 Organ-Specific Presentations

Pancreas - Autoimmune Pancreatitis (AIP) Type 1

• Most recognized manifestation; presents with obstructive jaundice (painless), new-onset diabetes, weight loss
• "Sausage-shaped" pancreas on imaging; capsule-like hypodense rim
• Must be distinguished from pancreatic adenocarcinoma (the most dangerous mimicker)

Salivary and Lacrimal Glands - Mikulicz Disease / IgG4-Related Dacryoadenitis and Sialadenitis

• Bilateral, painless, firm swelling of submandibular glands (predominantly); parotid and lacrimal glands also affected
• Distinguished from Sjögren syndrome: SSA/Ro negative, milder xerostomia, bilateral submandibular >parotid
• Male-to-female ratio ~1:1 (unusual for IgG4-RD overall)

Orbits - IgG4-Related Ophthalmic Disease

• Dacryoadenitis: enlargement of lacrimal gland causing superolateral periorbital swelling
• Orbital pseudotumor, extraocular muscle swelling, infra/supraorbital nerve swelling
• Exophthalmos in retrobulbar mass
• Rare: IgG4-related optic neuropathy (decreased visual acuity)
• Main differential: MALT lymphoma, Graves' disease, GPA, sarcoidosis

Biliary Tree - IgG4-Related Sclerosing Cholangitis (IgG4-SC)

• Frequently co-occurs with type 1 AIP
• Causes biliary strictures; must be distinguished from PSC and cholangiocarcinoma
• Transmural fibrosis with obliterative phlebitis and dense IgG4+ plasma cell infiltration
• Criteria: >10 IgG4+ cells/hpf (biopsy), >50/hpf (resection), IgG4+/IgG+ ratio >40%

Kidney - IgG4-Related Kidney Disease

• Most common: tubulointerstitial nephritis (TIN) - bilateral wedge-shaped or round hypodense cortical lesions on CT
• Less common: membranous glomerulonephritis (may present as nephrotic syndrome)
• Hypocomplementemia (low C3/C4) is characteristic
• May cause chronic renal insufficiency if untreated

Retroperitoneum - Retroperitoneal Fibrosis (RPF)

• Encasing periaortic fibrosis, often extends to ureters causing hydronephrosis
• Can cause ureteral obstruction and renal failure
• Hard to distinguish from idiopathic RPF (many cases of "idiopathic" RPF are IgG4-RD)

Aorta and Large Vessels - IgG4-Related Periaortitis/Aortitis

• Diffuse wall thickening of abdominal aorta; aneurysms
• Coronary artery involvement: wall thickening, stenosis, aneurysms, coronary ectasia - unique among systemic vasculitides affecting adults
• Periaortitis (abdominal) frequently accompanies RPF

Lungs - IgG4-Related Lung Disease

• Multiple patterns: nodules, consolidation, ground-glass opacities, peribronchovascular/septal thickening
• Paravertebral band-like soft tissue in thorax is a characteristic CT finding
• Differential: malignancy, sarcoidosis, Castleman disease, inflammatory myofibroblastic tumor

Meninges - IgG4-Related Hypertrophic Pachymeningitis

• Dura mater thickening; can cause headache, cranial nerve palsies, spinal cord compression
• Differential: GPA, sarcoidosis, lymphoma, inflammatory myofibroblastic tumor

Pituitary / Thyroid / Other

• IgG4-related hypophysitis: pituitary mass, hormonal deficiencies
• Riedel's thyroiditis: rock-hard thyroid, cervical structures compression, typically fibrotic subtype
• Prostate, skin (erythematous papules head/neck), breast, mesentery, mediastinum also reported

Lymphadenopathy

• Often asymptomatic, accompanies other organ involvement
• Usually responds well to corticosteroids
• Must rule out lymphoma (Castleman disease is a key mimic)

4.4 IgG4-RD as Variable-Vessel Vasculitis

• Large: aorta and its branches (periaortitis, aortitis)
• Medium: coronary arteries (unique adult vasculitic coronary involvement)
• Small: post-capillary venules (obliterative phlebitis - histologic hallmark)

5. Pathology - Histopathological Changes

5.1 Three Cardinal Histopathological Features

5.1.1 Dense Lymphoplasmacytic Infiltrate

• Prominent lymphoplasmacytic infiltrate rich in plasma cells and lymphocytes (particularly T cells)
• The plasma cells produce predominantly IgG4 antibodies
• Germinal centers with lymphoid follicles common in the proliferative subtype
• Eosinophils present in ~50% of cases

5.1.2 Storiform Fibrosis

• The fibrosis has an irregular, whorled ("cartwheel") pattern resembling a storiform arrangement
• Fibroblasts and myofibroblasts are embedded in the infiltrate
• The fibrosis is progressive and can completely replace normal tissue architecture
• More prominent in fibrotic subtype; may be absent in early disease

5.1.3 Obliterative Phlebitis

• Inflammatory infiltrate obliterates the lumen of veins (post-capillary venules and small veins)
• Vessel wall is destroyed; lumen occluded by inflammatory cells and fibrosis
• Found in the majority of cases; more prominent in fibrotic subtype
• Obliterative arteritis also occurs in some organs (especially lung)

5.2 Immunohistochemistry (IHC)

• IgG4+ plasma cell count: Critical metric
• >10 IgG4+ plasma cells/hpf in small biopsies
• >50 IgG4+ plasma cells/hpf in large resection specimens (highly suggestive)
• Some authors use >30/hpf as threshold for glandular tissue
• IgG4+/IgG+ plasma cell ratio >40% (most important ratio; >40% = supportive, the 2019 criteria weight >70% most heavily)
• Neither the count alone nor the ratio alone is diagnostic - requires clinicopathologic correlation

5.3 Additional Microscopic Findings

• Eosinophilic infiltrate: ~50% of biopsies
• Absence of features that argue against IgG4-RD: necrotizing vasculitis, prominent necrosis, granulomas, neutrophilic infiltration, macrophage/histiocytic proliferations
• Ductal organs show pipe-stem appearance with circumferential wall thickening
• Parenchymal organs (pancreas, kidney) show diffuse enlargement

5.4 Fibrotic Lesions - A Special Consideration

• As few as 10 IgG4+ cells/hpf may be regarded as supportive if clinical context is right
• The IgG4+/IgG+ ratio >40% retains importance even with low absolute counts
• Storiform fibrosis pattern becomes the dominant diagnostic clue

6. Diagnosis

6.1 Serum IgG4 Concentration

• Elevated serum IgG4 is supportive but neither sensitive nor specific
• Sensitivity of elevated serum IgG4 in biopsy-proven IgG4-RD: only ~50-60% when cases identified histologically; ~90% when cases identified by lab query
• Specificity issue: 27% of patients with serum IgG4 ≥5× ULN do NOT have IgG4-RD
• Prozone effect: In patients with dramatically elevated IgG4 (e.g., 4-5 g/dL), nephelometry may give spuriously low readings - additional dilutions required
• Serum IgG4 is most useful as a disease activity marker and for monitoring treatment response (falls with glucocorticoid treatment)
• Other IgG subclasses (IgG1, IgG2, IgG3) are often co-elevated but IgG4 elevation is usually disproportionate

6.2 Other Laboratory Findings

• Plasmablasts (CD19+CD38+CD20-CD27+): elevated circulating plasmablasts are a sensitive biomarker of active disease, more reliable than serum IgG4 in some studies
• Eosinophilia: common, especially in proliferative subtype
• Hypocomplementemia (low C3, C4): particularly with renal involvement, may suggest immune complex deposition
• Elevated IgE: may exceed 10× ULN
• ESR/CRP: often normal or mildly elevated (not reliable markers)
• ANA, ANCA, RF: negative (positive results should prompt alternative diagnosis)

6.3 Imaging

• CT/MRI: identifies mass lesions, diffuse organ enlargement, characteristic patterns (sausage pancreas, bilateral renal cortex lesions, periaortic soft tissue, RPF)
• 18F-FDG PET/CT: maps multiorgan involvement, distinguishes active inflammatory lesions from established fibrosis, guides biopsy, monitors treatment response. Active IgG4-RD shows increased FDG uptake
• MRCP: demonstrates biliary strictures in IgG4-SC
• Endoscopic ultrasound: used for pancreatic/biliary biopsy

6.4 Histopathology/Biopsy

• Biopsy with IHC remains the gold standard for definitive confirmation
• Adequate specimen size is critical (small endoscopic biopsies may be non-diagnostic)
• Core needle biopsy often sufficient for accessible lesions
• Lacrimal gland, minor salivary gland, and submandibular gland biopsies are often the most accessible with high diagnostic yield

6.5 Integrated Diagnostic Approach

1. Clinical presentation + appropriate organ involvement
2. Exclude malignancy, infection, and alternative autoimmune diagnoses
3. Serum IgG4 + other labs
4. Cross-sectional and functional imaging
5. Tissue biopsy with IHC (in most cases)
6. Apply ACR/EULAR classification criteria (score ≥20)
7. Response to glucocorticoid trial can support diagnosis (lack of response argues strongly against)

7. The IgG4-RD Responder Index (IgG4-RD RI)

7.1 Background and Development

• IgG4-RD is a multiorgan disease followed by multiple specialties
• Divergent approaches to assessment complicated interpretation of studies
• No validated outcome measure existed for disease activity and treatment response

7.2 Structure of the IgG4-RD RI

1. Lists all organ systems that can be involved in IgG4-RD (24 organ domains including: orbital/periorbital, salivary glands, lymph nodes, thyroid, lungs, aorta, pericardium, pancreas, biliary tree, kidneys, retroperitoneum, pachymeninges, skin, etc.)
2. For each organ system, the physician rates disease activity on a three-level scale:

• 2 = Active disease, new or worsening (within the past 30 days)
• 1 = Improved but still active (compared to prior assessment)
• 0 = No activity at that site

1. Physician Global Assessment (PGA): An overall 0-10 visual analog scale is included as a cross-check
2. Damage items: The index distinguishes between "disease activity" and "disease damage" - damage (irreversible changes due to scarring/fibrosis, scored separately) does not fluctuate with treatment

7.3 Scoring and Interpretation

• Total IgG4-RD RI score = sum of scores across all active organ domains
• Higher score = more active, more widespread disease
• Complete remission is defined as an IgG4-RD RI score of 0 (no active disease in any organ)
• Flare is typically defined as recurrence of disease activity (increase in score) after a period of remission
• In clinical trials (e.g., the MITIGATE rituximab and inebilizumab trials), the IgG4-RD RI served as the primary or key secondary efficacy outcome
• In the ACR Convergence 2025 data, the mean Responder Index in an active disease cohort was 6.09 (CI 4.63-7.55)
• Serum IgG4 and IL-5 levels correlated most significantly with the Responder Index score

7.4 International Validation

7.5 IgG4-RD Damage Index

8. Management

8.1 Indications for Treatment

• Active, symptomatic IgG4-RD in any organ
• Asymptomatic but progressive disease in vital organs (pancreas, kidney, biliary tree, aorta, meninges)
• Disease threatening organ function even if clinically silent

8.2 Remission Induction - Glucocorticoids

• Starting dose: prednisone 0.6 mg/kg/day (typically 30-40 mg/day)
• Maintained for 2-4 weeks, then tapered
• Goal: complete cessation within 10-16 weeks (some Asian centers maintain 5-10 mg/day for years)
• Response is typically swift (within days to weeks), especially in proliferative subtype
• Failure to respond = reconsider diagnosis
• Limitation: responses are often temporary; relapse is frequent, especially in multiorgan disease with high baseline IgG4

• Typical patient demographics (elderly, often diabetic, hypertensive, obese, osteoporotic)
• Pancreatic IgG4-RD itself causes glucose intolerance

8.3 Conventional DMARDs (Steroid-Sparing)

• Mycophenolate mofetil
• Azathioprine
• Methotrexate
• 6-mercaptopurine

8.4 Biologic Agents

Anti-CD20 (Rituximab) - Anti-B Cell

• Rituximab (two 1-gram IV doses 2 weeks apart) produced significant clinical benefit in the landmark prospective open-label trial (Carruthers et al., 2015, Ann Rheum Dis [PMID: 25667206])
• 29 of 30 patients showed efficacy; 77% achieved remission off prednisone at 6 months
• Relapses common by 12 months - retreatment required
• Serum IgG4 monitoring guides retreatment timing
• Mechanism: B cell depletion interrupts antigen presentation to CD4+ CTLs; reduces myofibroblast activation

Anti-CD19 (Inebilizumab) - The MITIGATE Trial - NEJM 2025

• Design: Double-blind, randomized, placebo-controlled, 52-week trial
• n = 135 patients; inebilizumab (300 mg IV on days 1, 15, week 26) vs. placebo; both groups received identical glucocorticoid tapers
• Primary endpoint: Time to first treated, adjudicated flare

• Inebilizumab depletes CD19+ B cells (broader B cell depletion than rituximab, which targets CD20; CD19 is expressed on plasmablasts and plasma cell precursors not targeted by CD20)
• This trial confirms CD19-targeted B cell depletion as a major treatment advance in IgG4-RD

Anti-CTLA4 (Abatacept)

• Open-label trial of 10 patients showed modest evidence of efficacy
• Most appropriate for mild disease; not optimal without glucocorticoids or for multiorgan disease

Emerging Therapies

• Obexelimab (anti-CD19/Fc-γRIIb): Phase II trial - positive responses in 12/15 patients without glucocorticoids; Phase III ongoing
• Elotuzumab (anti-SLAMF7): SLAMF7 expressed on both CD4+ CTLs and B cells - proof-of-concept trial initiated
• Cytokine targeting: IL-13, IL-21, IL-5, IFN-γ pathways under investigation

8.5 Treatment Algorithm Summary

Active IgG4-RD
        |
Glucocorticoids (Prednisone 0.6 mg/kg/day, taper over 10-16 weeks)
        |
    [Achieved remission?]
   YES              NO
    |                |
Maintenance:    Reconsider diagnosis
- Watch/wait    If confirmed: B cell depletion
- Steroid-      (Rituximab or Inebilizumab)
  sparing DMARD
        |
  [Relapse?]
      |
B cell depletion (Rituximab/Inebilizumab)
± retreatment guided by serum IgG4 + clinical assessment (IgG4-RD RI)

9. Differential Diagnosis by Organ

10. Nomenclature of IgG4-RD by Organ

Key References

1. Firestein & Kelley's Textbook of Rheumatology, 2-Volume Set - Chapter 126: IgG4-Related Disease (comprehensive sections on histology, pathogenesis, vasculitis, classification, and treatment)
2. Robbins & Cotran Pathologic Basis of Disease (10th ed., 2023) - Chapter 6: IgG4-RD histopathology and immunology
3. Rheumatology, 2-Volume Set (Elsevier, 2022) - Chapters 178, 179: organ manifestations
4. Carruthers MN, Stone JH, Deshpande V, Khosroshahi A. Development of an IgG4-RD Responder Index. Int J Rheumatol 2012 [PMID: 22611406]
5. Perugino CA, Stone JH. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat Rev Rheumatol 2020 [PMID: 32939060]
6. Stone JH, Khosroshahi A, Zhang W, Della-Torre E, Okazaki K, Tanaka Y, et al. Inebilizumab for Treatment of IgG4-Related Disease (MITIGATE Trial). N Engl J Med 2025 Mar 27 [PMID: 39541094] - Phase III RCT; HR 0.13 for flare risk with inebilizumab
7. Peyronel F, Della-Torre E, Maritati F, et al. IgG4-related disease and other fibro-inflammatory conditions. Nat Rev Rheumatol 2025 May [PMID: 40195520]
8. Lanzillotta M, Culver E, Sharma A, et al. Fibrotic phenotype of IgG4-related disease. Lancet Rheumatol 2024 Jul [PMID: 38574746]

Recent Evidence Update (2024-2026): The MITIGATE Phase III RCT (NEJM 2025) represents the highest quality evidence yet in IgG4-RD management, demonstrating that inebilizumab (anti-CD19) reduces flare risk by 87% (HR 0.13, P<0.001) and nearly quintuples the odds of glucocorticoid-free complete remission compared to placebo. This establishes CD19-targeted B cell depletion as a potential standard of care for relapsing/refractory IgG4-RD. The 2025 Nature Reviews Rheumatology review also clarifies the differential diagnosis framework against histiocytoses, lymphoproliferative disorders, and systemic vasculitides.