IgG4-Related Disease

Lab Workup

• Can be helpful to evaluate for organ involvement, associated organ damage, and prognostic markers
• Elevated serum IgG4 concentration supports a diagnosis of IgG4-RD, but is neither sensitive nor specific for the diagnosis; up to 30% of patients have a normal serum IgG4 concentration.
• An elevated lipase (pancreatic disease), bilirubin (pancreatobiliary disease), or creatinine (renal disease) may point to specific manifestations; low C3 or C4 may suggest renal disease but is not specific.
• Low fecal elastase, micronutrient deficiencies (e.g., vitamin D or Zinc), and elevated A1c may suggest pancreatic insufficiency
• Additional testing is guided by the differential diagnosis and may include ANA and associated autoantibodies (e.g., SSA, SSB, dsDNA), ANCA, TB testing, HIV
• Serum protein electrophoresis (SPEP)
• IgG subclasses
• IgE

Imaging

• Cross-sectional imaging of the chest, abdomen, and pelvis is typically performed to screen for organ involvement (e.g., pancreatitis, retroperitoneal fibrosis)
• Imaging of the head/neck may be considered if there are signs/symptoms suggestive of manifestations in the cranium (e.g., hypertrophic pachymeningitis), orbit, or salivary glands (view images)

Biopsy is key! (view image)

• Biopsy may not be feasible depending on the location, and a small biopsy may not reveal all features but can be helpful to rule out malignancy and other mimicking conditions.
• An infiltrate of IgG4+ plasma cell (measured by cells per high powered field and proportion of all plasma cells) supports the diagnosis but is not specific.
• Typical histopathologic findings: lymphoplasmocellular inflammation, storiform fibrosis, obliterative phlebitis; atypical features that suggest an alternative diagnosis include necrosis, vasculitis, prominent neutrophil or histiocytic infiltrates
• Lymph node histopathology and immunostaining is not typically specific for the diagnosis of IgG4-RD.

• Malignancy should be ruled out in the case of a solitary mass (e.g., pancreatic mass, dominant salivary gland enlargement/nodule, lung mass)
• Sjogren’s disease, sarcoidosis, inflammatory bowel disease, ANCA-associated vasculitis, and other conditions can also cause salivary gland enlargement and other similar manifestations
• Primary sclerosing cholangitis is not steroid-responsive and can be distinguished from IgG4-related cholangitis.
• Castleman disease
• ANCA-associated vasculitis, Takyasu arteritis, Behcet’s syndrome
• Sarcoidosis
• Infection: fungal (histoplasmosis, etc.), viral (HIV), bacterial (TB, etc.)

• Very sensitive to corticosteroids but often relapse during steroid taper or after discontinuation!
• Rituximab can be quite effective.
• Other immunosuppressives (methotrexate, azathioprine, mycophenolate) can also be used.
• Management may also include biliary or ureteral stenting, pancreatic enzyme replacement therapy, surgical debulking for highly fibrotic lesions, and other organ-specific interventions.

• Early treatment helps prevent additional organ damage.
  
• Consider osteoporosis treatment/prophylaxis for those on long-term systemic steroids.
• For people with endocrine or exocrine pancreatic insufficiency, insulin, enzyme replacement therapy, and other interventions may be necessary.
• Following imaging is often used, based on manifestations, to monitor response to treatment and to assess for recurrence.

• Labs (even serum IgG4) have limited utility.
• Clinicopathologic correlation is key, and biopsy, when possible, can be useful for establishing the diagnosis and excluding mimicking conditions.
• Generally very steroid responsive – consider other diagnoses if not responding to steroids
• Disease relapses are common.
• New disease manifestations can occur over time.
• Rituximab can help considerably.