Immunoglobulin G4-related disease

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterised by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and tissue infiltration by IgG4-positive plasma cells. It can affect virtually any organ, most commonly the pancreas, salivary glands, bile ducts, orbits, kidneys, lungs, and aorta. IgG4-RD was only recognised as a unified systemic disease in the early 2000s and is now understood to encompass previously described conditions including autoimmune pancreatitis type 1, Mikulicz disease, Riedel thyroiditis, and orbital pseudotumour. The condition is more common in older males and typically responds dramatically to corticosteroids, though relapse is common.

The pathogenesis of IgG4-RD involves aberrant immune activation with a T helper 2 (Th2) and regulatory T cell (Treg) skewed immune response leading to fibrosis and IgG4 plasma cell accumulation. The role of IgG4 antibodies themselves in pathogenesis remains unclear — they may be a reactive epiphenomenon rather than directly pathogenic. Recent data suggest activated CD4+ cytotoxic T cells (CTL) are central effector cells driving fibrosis.

Key Pathogenic Mechanisms

• T follicular helper (Tfh) cells drive B cell class switching to IgG4 via IL-4 and IL-13
• Regulatory T cells (Tregs) produce IL-10 and TGF-β — promoting fibrosis and IgG4 switching
• CD4+ cytotoxic T lymphocytes (CTLs) — recent evidence suggests these are key drivers of tissue damage and fibrosis
• Storiform fibrosis — characteristic "cartwheel" fibrosis pattern driven by TGF-β; resistant to glucocorticoids once established
• Obliterative phlebitis — inflammation and fibrosis of venules; pathognomonic histological finding
• IgG4 antibodies: biologically inert (non-complement fixing); their presence is a reactive marker, not necessarily directly pathogenic

Histological Hallmarks

IgG4-RD typically presents as a subacute to chronic mass-forming or infiltrative lesion in one or more organs. The clinical presentation depends on the organs affected. Constitutional symptoms (fever, weight loss) are uncommon and should prompt consideration of malignancy. The great clinical challenge is that IgG4-RD closely mimics cancer, lymphoma, and other inflammatory conditions.

Organ-Specific Manifestations

Red Flags Suggesting Alternative Diagnosis

• Fever and constitutional symptoms — uncommon in IgG4-RD; suggest malignancy, lymphoma, or infection
• Rapid progression — IgG4-RD is typically subacute; rapid growth suggests cancer
• Very high CA 19-9 — raises concern for pancreatic adenocarcinoma
• Cytopenia — uncommon in IgG4-RD; suggests lymphoma or autoimmune cytopenias
• No response to glucocorticoids — reconsider diagnosis; biopsy if not already done
• Markedly elevated serum IgG4 alone — serum IgG4 can be elevated in pancreatic cancer, cholangiocarcinoma, atopic disease, and other conditions

Investigations in IgG4-RD aim to confirm the diagnosis, assess organ involvement, exclude malignancy and mimics, and establish baseline for treatment monitoring.

• Essential
  Serum IgG4 level

  Elevated (>1.35 g/L) in 60–70% of cases. Sensitivity ~90% in multi-organ disease but lower in single-organ. Very high levels (>5× ULN) are highly specific. Normal level does not exclude IgG4-RD.
• Essential
  Serum IgG subclasses (IgG1–4)

  IgG4 subclass — assess level and proportion of total IgG. Elevated IgG4/IgG ratio supports diagnosis.
• Essential
  FBC, UEC, LFTs, GGT, ALP, bilirubin

  Baseline; assess organ involvement. Elevated ALP/GGT/bilirubin with IgG4 cholangitis. Elevated creatinine with renal involvement.
• Essential
  Urinalysis and urine protein:creatinine ratio

  Renal involvement — tubulointerstitial nephritis may cause proteinuria and haematuria.
• Essential
  Lipase and amylase

  Assess pancreatic involvement; may be mildly elevated or normal in AIP-1.
• Essential
  CT chest/abdomen/pelvis (with contrast)

  Assess extent of disease. Pancreatic enlargement, biliary strictures, renal lesions, retroperitoneal fibrosis, lymphadenopathy, pulmonary nodules. Required before biopsy planning.
• Essential
  Tissue biopsy with IgG4 immunostaining

  Gold standard. IgG4+ plasma cells with storiform fibrosis and obliterative phlebitis confirms diagnosis. Must exclude lymphoma and carcinoma on pathology.
• Recommended
  MRI pancreas/MRCP

  Better delineation of pancreatic duct (AIP-1: diffuse narrowing vs. focal; PSC: beading). Guides management of biliary involvement.
• Recommended
  PET-CT (FDG)

  Assesses multi-organ involvement and disease activity. Useful when disease extent unclear or to monitor treatment response. Not routine — refer to specialist.
• Recommended
  Autoantibody screen (ANA, ANCA, anti-SSA/SSB, anti-dsDNA)

  Exclude overlap with SLE, Sjögren syndrome, ANCA vasculitis, primary biliary cholangitis.
• Recommended
  Serum complement (C3, C4)

  Low C3/C4 supports IgG4-RD (particularly with renal involvement) and distinguishes from conditions with normal complement.
• Recommended
  CA 19-9, CEA

  Tumour markers — elevated CA 19-9 raises concern for pancreatic adenocarcinoma or cholangiocarcinoma; must be interpreted in context.
• Recommended
  Bone marrow biopsy

  If lymphoma suspected — cytopenias, lymphadenopathy, or atypical features on tissue biopsy.

2019 ACR/EULAR Classification Criteria

The 2019 ACR/EULAR classification criteria for IgG4-RD provide a points-based system using entry criteria (characteristic histology or radiology), exclusion criteria (features favouring an alternative diagnosis), and inclusion criteria (clinical, serological, radiological, and pathological features). A score of ≥20 classifies IgG4-RD. These criteria are for classification (research) purposes; clinical diagnosis is based on the overall picture including tissue pathology.

Risk stratification in IgG4-RD is based on organs involved, degree of organ dysfunction, and risk of irreversible damage if untreated.

IgG4-RD Responder Index (IgG4-RD RI)

• Validated disease activity scoring tool — assesses activity and damage in each affected organ
• Used in specialist rheumatology practice and clinical trials to monitor treatment response
• Scores each organ site for activity (0=absent, 1=mild, 2=moderate, 3=severe) and damage (D)
• Useful for baseline documentation and monitoring steroid taper response

Glucocorticoids are the cornerstone of IgG4-RD treatment and produce dramatic responses in the majority of patients. However, relapse is common after discontinuation, and steroid-sparing agents are often required for long-term maintenance. All treatment decisions should be made in consultation with a rheumatologist or specialist experienced in IgG4-RD.

First-Line — Glucocorticoids

Steroid-Sparing Agents (Maintenance / Relapsing Disease)

Directed therapy in IgG4-RD addresses organ-specific complications and procedures required alongside systemic immunosuppression.

Autoimmune Pancreatitis Type 1 (AIP-1)

• Distinguishing AIP-1 from pancreatic adenocarcinoma is critical — ERCP, EUS with biopsy, and serum IgG4 are key
• Characteristic ERCP findings in AIP-1: diffuse irregular narrowing of main pancreatic duct (vs. abrupt cutoff in cancer)
• HISORt criteria (Mayo Clinic) or Japanese criteria can support diagnosis without biopsy in typical presentations
• Prednisolone induction: 0.6 mg/kg/day for 2–4 weeks — dramatic improvement distinguishes from cancer
• Biliary stenting may be required for obstructive jaundice — can be removed after glucocorticoid response
• Exocrine pancreatic insufficiency — pancreatic enzyme replacement therapy (PERT) if symptomatic steatorrhoea
• Endocrine insufficiency — new-onset diabetes may resolve with treatment or persist — monitor HbA1c

Retroperitoneal Fibrosis and Periaortitis

• Ureteric obstruction — may require ureteric stenting or nephrostomy before or during glucocorticoid therapy
• Aortic involvement — large vessel imaging (CT angiography or MRI) for aortitis, aneurysm screening
• Vascular surgery referral if aortic aneurysm ≥5 cm or rapidly enlarging
• Fibrosis may not fully resolve — residual scarring can persist even after successful immunosuppression

Orbital IgG4-RD

• Ophthalmology co-management — assess visual acuity, visual fields, intraocular pressure
• Orbital decompression if severe proptosis causing corneal exposure or optic nerve compression
• Radiotherapy — low-dose orbital radiation used for refractory orbital IgG4-RD; effective but specialist only

Renal IgG4-RD

• Renal biopsy confirms tubulointerstitial nephritis — required before immunosuppression if diagnosis uncertain
• Glucocorticoids may prevent progression to renal fibrosis — early treatment important
• Nephrology co-management for all cases of IgG4-related renal disease
• Monitor eGFR and proteinuria regularly; renal impairment may partially recover with treatment

Non-pharmacological management in IgG4-RD focuses on corticosteroid complication prevention, patient education, and multidisciplinary coordination across the multiple organs that may be affected.

Corticosteroid Complication Prevention

• Bone protection — calcium 600–1200 mg/day + vitamin D 1000–2000 IU/day for all patients on corticosteroids; bisphosphonate if prolonged course or high fracture risk
• DXA bone density — baseline and annually for prolonged corticosteroid use
• Blood pressure monitoring — hypertension is a common corticosteroid side effect
• Glucose monitoring — fasting glucose or HbA1c; steroid-induced diabetes common in older patients
• Weight and cardiovascular risk — dietary counselling; limit weight gain
• Pneumocystis prophylaxis (cotrimoxazole) — consider if prolonged high-dose corticosteroids or combination immunosuppression
• Vaccinations — influenza annually; pneumococcal vaccine before or during early immunosuppression; live vaccines contraindicated on immunosuppression

Patient Education and Monitoring

• Educate patients about IgG4-RD — chronic condition with high relapse rate; long-term follow-up required
• Symptom diary — document new symptoms that may indicate relapse or new organ involvement
• Dietary advice during corticosteroid treatment — low sodium diet; diabetic diet if glucose impaired
• Alcohol avoidance — particularly important with pancreatic and hepatobiliary involvement

Multidisciplinary Involvement

• Rheumatology — disease coordination and steroid-sparing strategy
• Gastroenterology/hepatology — pancreatic and biliary disease; ERCP; EUS biopsy
• Nephrology — renal involvement monitoring
• Ophthalmology — orbital disease
• Vascular surgery — aortitis, aneurysm
• Urology — retroperitoneal fibrosis, ureteric obstruction
• Endocrinology — diabetes, pancreatic exocrine insufficiency, hypopituitarism
• Radiology — PET-CT staging, organ-specific imaging

Monitoring in IgG4-RD tracks treatment response, relapse, and complications of immunosuppression.

When to Refer

• Rheumatology: All cases of IgG4-RD — specialist management required for diagnosis, treatment initiation, and relapse management
• Gastroenterology/Hepatology: All pancreatic or biliary involvement — ERCP, EUS biopsy, biliary stenting
• Nephrology: Renal involvement or unexplained renal impairment
• Ophthalmology: Orbital involvement, visual symptoms
• Vascular surgery: Aortitis or periaortic disease with aneurysmal change
• Urology: Retroperitoneal fibrosis causing ureteric obstruction or hydronephrosis
• Haematology/oncology: If lymphoma cannot be excluded on biopsy or clinical grounds

Several subgroups of IgG4-RD patients require modified approaches to diagnosis and management.

Older Adults with IgG4-RD

• IgG4-RD is most common in older males — the demographic most at risk of malignancy; vigilance for concurrent cancer is essential
• Higher risk of corticosteroid-related complications — diabetes, osteoporosis, hypertension, cataract
• Consider rituximab earlier to minimise cumulative steroid exposure
• Frailty and polypharmacy — review drug interactions with immunosuppressants

IgG4-RD with Malignancy History

• Prior or concurrent malignancy does not exclude IgG4-RD — the conditions can coexist
• Thorough oncological review required before initiating immunosuppression
• Close surveillance — ongoing monitoring for cancer recurrence or new malignancy

Hypertrophic Pachymeningitis / CNS IgG4-RD

• Rare but severe — cranial nerve palsies, headache, visual loss, pituitary dysfunction
• MRI brain/spine with contrast — meningeal thickening, dural masses, pituitary stalk thickening
• High-dose corticosteroids required — IV methylprednisolone pulse for acute presentations
• Neurosurgery consultation if mass effect or hydrocephalus

Seronegative IgG4-RD (Normal Serum IgG4)

• Normal serum IgG4 in 30–40% of biopsy-confirmed cases — diagnosis relies on histology
• Tissue biopsy is essential in seronegative presentations — do not withhold biopsy based on normal serology
• Monitor with imaging and clinical assessment rather than serum IgG4 in seronegative patients

Stewardship in IgG4-RD focuses on ensuring accurate diagnosis before treatment, minimising glucocorticoid exposure, and using steroid-sparing agents appropriately in relapsing disease.

GP Role

• Recognise potential IgG4-RD — mass-forming lesion in pancreas, orbit, salivary glands, or retroperitoneum in an older male should prompt IgG4 serology and specialist referral
• Avoid empirical corticosteroids before specialist assessment — exclude malignancy first
• Initial investigations: serum IgG4, IgG subclasses, FBC, UEC, LFTs, lipase, urinalysis, CT chest/abdomen/pelvis
• Urgent rheumatology/gastroenterology referral for suspected IgG4-RD
• Long-term monitoring of corticosteroid complications in primary care — glucose, BP, bone density, weight
• Coordinate vaccinations before immunosuppression
• Monitor for relapse during and after glucocorticoid taper — liaise with rheumatologist if IgG4 rising or symptoms recur

IgG4-RD requires long-term follow-up — relapse occurs in 40–60% of patients, particularly after glucocorticoid cessation. Ongoing monitoring is essential to detect relapse early and minimise organ damage.

Remission and Treatment Cessation

• Remission: normalised serum IgG4 + no active lesions on imaging + clinical resolution for ≥6 months
• Attempt glucocorticoid cessation after sustained remission — taper very slowly over months
• Many patients require indefinite low-dose maintenance or rituximab cycles due to relapsing course
• Risk factors for relapse: proximal biliary involvement, multi-organ disease, elevated IgG4 at time of treatment withdrawal, short induction course

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