IgG4-related Disease

Background

• Immunoglobulin (Ig)G4-related disease is a chronic fibroinflammatory condition of unknown etiology associated with single or multi-organ swelling and subsequent fibrosis, characterized by infiltration of CD4 T cells and IgG4⁺ plasmablasts.
• IgG4-related disease is an uncommon condition, though probably underrecognized and underreported. Middle-aged to elderly men are most frequently affected.
• IgG4-related diseases represent a wide array of apparently disparate conditions, affecting nearly every organ in the body.
• More common presentations include sialadenitis, dacryoadenitis, lymphadenopathy, type 1 autoimmune pancreatitis, kidney disease, lung involvement, liver and biliary tract disease, retroperitoneal fibrosis, and orbital disease.
• Genetic and environmental factors have been linked to IgG4-related disease, including human leukocyte antigen haplotypes, cytotoxic T lymphocyte antigen 4 polymorphisms, genes associated with pancreatic injury, and long-term exposure to solvents, metal dusts, pigments, and oils.

Evaluation

• IgG4-related disease may be asymptomatic for months or years before diagnosis, with vacillating progression of organ dysfunction that may include periods of remission and emergence of new organ involvement leading to multi-organ syndrome.
• Presentation depends on the organ(s) involved. For example
  • patients with pancreatitis may present with obstructive jaundice, abdominal pain, and pruritus
  • patients with orbital/periorbital disease may present with proptosis and lacrimal gland swelling
  • patients with lung involvement may present with cough, dyspnea, chest pain, and fever
• Physical exam may reveal fever, erythematous papules, plaques, and nodules (especially on head and neck), lacrimal gland swelling, salivary gland swelling, thyroid enlargement, or enlarged lymph nodes.
• Suspect IgG4-related disease in patients with unexplained enlargement of ≥ 1 organ or in adults with new-onset autoimmune pancreatitis. Ruling out malignancy is nearly always necessary.
• Diagnosis relies on tissue biopsy with histopathology and immunostaining, imaging studies to assess extent of organ involvement, and measurement of serum IgG4 levels.
  • Comprehensive diagnostic criteria utilize diffuse or localized organ swelling, serum IgG4 levels, and histopathologic findings to categorize as definitive, probable, or possible IgG4-related disease.
  • Pathology consensus criteria utilizes histopathologic features and semiquantitative assessment of IgG4⁺ plasmablasts to categorize as highly suggestive, probable, or insufficient histologic IgG4-related disease.
  • Detailed organ-specific criteria have been developed which utilize a combination of histology, serology, and imaging to categorize as definitive, probable, or possible IgG4-related disease.

Management

• Patients with asymptomatic disease and no organ dysfunction, including those in spontaneous remission, may not require therapy.
• Treatment indicated in all patients with symptomatic, active IgG4-related disease and some patients with asymptomatic disease require therapy (Weak recommendation).
• Urgent therapy warranted in patients with aortic involvement, retroperitoneal fibrosis, proximal biliary strictures, tubulointerstitial nephritis, pachymeningitis, pancreatic enlargement, and pericarditis.
• Glucocorticoids are the mainstay of therapy unless contraindicated (Weak recommendation).
  • Typical dosing is prednisolone 0.6 mg/kg/day for 2-4 weeks followed by gradual taper over 3 to 6 months to 2.5-5 mg/day, which is maintained for up to 3 years.
  • Failure to respond to glucocorticoids should raise suspicion for other diagnoses, especially malignancy.
• Glucocorticoid therapy plus steroid-sparing immunosuppressive agent, such as azathioprine, mycophenolate, mofetil, 6-mercaptopurine, methotrexate, tacrolimus, cyclophosphamide, and rituximab (anti-CD20) may be considered for patients with refractory or complicated disease (Weak recommendation).
• Relapse is common, occurring in 15%-33% of patients.
• Glucocorticoid maintenance therapy may be beneficial in patients with organ-threatening dysfunction, history of relapse, or higher risk of relapse (significantly elevated IgG4 levels, proximal bile duct involvement) (Weak recommendation).
• For patients who relapse, retreatment with glucocorticoids and introduction of steroid-sparing agent is indicated (Weak recommendation).
• Surgery may be indicated in patients with infiltrative processes of biliary tree or urethra, lymphadenopathy, masses in other solid organs, or ocular/submaxillary tumors.
• Follow-up studies may include
  • measurement of serum IgG4 levels, usually after 2 weeks of therapy, although levels do not always correlate with disease activity
  • imaging studies to monitor disease activity, especially in patients with pulmonary, biliary, pancreatic, and kidney involvement
• Prognosis is highly dependent on organ(s) involved. Potential complications include secondary diabetes in those with pancreatitis, and other end-organ dysfunction and failure secondary to fibrosis.