IgG4-related disease (IgG4-RD)

Background

Multi-organ, immune-mediated fibrotic disease characterized by diffuse or focal organ enlargement with tumor-like mass formation secondary to massive infiltration of IgG4- positive plasma cells with storiform fibrosis
Incidence: usually >60y; more often affects men
Prevalence: unclear but quite rare; pancreatic involvement most common
Etiology: poorly understood; genetic predisposition + environmental factors lead to CD4+ T cell and B cell activation that stimulate fibroblasts and promote tissue remodeling through unclear mechanisms

Usually subacute related to gradual progressive enlargement of affected organ(s) or found incidentally. Fevers and acute illness are not expected features.
Presentation highly variable, dependent on affected organ:
- Pancreas ("type 1 autoimmune pancreatitis”): painless obstructive jaundice, mild abdominal discomfort, weight loss; rarely acute pancreatitis
- Biliary duct: obstructive jaundice
- Glands (lacrimal, salivary; “Mikulicz disease:):
- Retroperitoneum: periaortic inflammation, ureter compression
- Also: central nervous system, thyroid gland, lungs, liver, gastrointestinal tracts, kidneys, prostate, mesentery, lymph nodes, etc.
2+ organ involvement most often (60-90%)

Serologic: IgG4 (fairly sensitive: >130mg/dL in 70-80%; at higher levels, very specific: if >280mg/dL, 99%), elevated ESR and CRP, +ANA (nonspecific but seen in 50%), elevated RF (nonspecific but seen in 20%), low C3/4 (particularly in renal and pancreas involvement)
Gold standard: biopsy of affected organ with abundant infiltration of IgG4-positive plasma cells and lymphocytes, storiform fibrosis, and obliterative phlebitis
ACR/EULAR classification criteria can help guide diagnosis (meets criteria if entry criteria met, no exclusion criteria present, total points ≥20):
- (1) Entry: clinical or radiologic involvement of a classically affected organ OR pathologic evidence of inflammatory process with lymphoplasmacytic infiltrate
- (2) Exclusion: clinical (fever, absence of objective response to steroids), serologic (numerous including presence of several other autoantibodies, peripheral eosinophilia, etc.), radiologic (findings suspicious for malignancy, rapid interval progression, RHEUMATOLOGY 595 splenomegaly), pathologic (findings suggestive of alternative pathology), known alternative diagnosis (multicentric Castleman’s disease, etc.)
- (3) Inclusion criteria: consistent features on histopathology (0-13), IgG4 immunostaining (0-16), serum IgG4 (0-11), glandular involvement (0-14), chest (0-10), pancreas and biliary tree involvement (0-19), renal involvement (0-10), retroperitoneal involvement (0-8)

Indications for treatment: (1) demonstrated or anticipated organ damage, (2) high disease activity, (3) symptomatic relief.
Consider watchful waiting in those with mild, asymptomatic disease or stable remission
Induction: oral prednisolone starting at 0.6 mg/kg/day, x2–4 weeks, followed by gradual taper over 2-3 months to maintenance dose
Organ-specific management (e.g. biliary stenting)
Monitoring: highly individualized based on number and severity organ involvement, initial IgG4 level, initial response to steroids (can use IgG4-RD Responder Index scores to help guide) but combination of symptoms, IgG4 levels, imaging (CT/MRI/PET) - Maintenance: oral prednisolone 2.5–5 mg/day; depending on medical comorbidities, may continue indefinitely versus attempt taper within 3 years
Relapse: Re-induction with steroids and/or steroid-sparing agents (azathioprine, mycophenolate mofetil, methotrexate, rituximab)