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IgG4-related Disease and Lung Involvement

IgG4-related Disease and Lung Involvement. Jay H. Ryu Division of Pulmonary and Critical Care Medicine Mayo Clinic, Rochester, Minnesota, USA. IgG4-related Disease (IgG4-RD). Idiopathic fibroinflammatory disorder, multi-system.

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IgG4-related Disease and Lung Involvement

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  1. IgG4-related Disease and Lung Involvement Jay H. Ryu Division of Pulmonary and Critical Care Medicine Mayo Clinic, Rochester, Minnesota, USA

  2. IgG4-related Disease (IgG4-RD) • Idiopathic fibroinflammatory disorder, multi-system. • Initially described in 2001, “autoimmune pancreatitis” (type 1 AIP) • Lymphoplasmacytic infiltration with IgG4+ plasma cells and fibrosis, high serum IgG4 level. • IgG4-related lesions in many other organs identified. • Can be localized to one or more sites. • Usually adults, more often men.

  3. IgG4-related DiseaseKey Clinical Points • Autoimmune disease? • Wide spectrum of clinical and radiologic presentations involving any organ(s) • Can be PET-positive • Corticosteroid-responsive disease

  4. (Umehara et al. Mod Rheumatol 2012)

  5. Current Diagnosis of IgG4-RD • 2 of 3 major histopathological features: • Dense lymphoplasmacytic infiltrate • Fibrosis, at least focally storiform • Obliterative phlebitis • Immunohistochemical - ↑ number of IgG4+ plasma cells (>10 to >50 depending on organ) and ↑ IgG4+/IgG+ cell ratio (>40%). AND • Clinical context – presentation, serum IgG4 level, response to steroids. (Deshpande et al. Mod Pathol 2012)

  6. IgG4 AIP1 >25/hpf; 3+

  7. Storiform Fibrosis (IgG4-related Orbital Pseudotumor) (Deshpande et al. Mod Pathol 2012)

  8. Obliterative Phlebitis (AIP type 1) (Deshpande et al. Mod Pathol 2012)

  9. Obliterative Phlebitis (AIP type 1) (Deshpande et al. Mod Pathol 2012)

  10. Pulmonary Manifestations of IgG4-RD • Intrathoracic manifestations reported in 14% to >50%. • Can present as sole manifestation. • Symptomatic in ~1/2, eg, cough dyspnea, pain. • Elevated serum IgG4 level – common. • Can be PET-positive. • Responds to corticosteroid therapy.

  11. IgG4-related DiseaseIntrathoracic Manifestations • Parenchymal lesions • Focal opacities (pseudotumor) • Interstitial lung disease (OP, NSIP) • Mediastinal / hilar lymphadenopathy • Mediastinal fibrosis • Airway (stenosis) • Pleural (nodules, effusion) * Some patients exhibit multiple findings. (Ryu et al. ERJ 2012)

  12. IgG4-RD: Focal Opacities 69M ex-smoker - cough, fevers, & L lung lesion (2008), h/o AIP treated with steroids 2 yrs before Bronchoscopic bx – nondiagnostic Surgical lung biopsy  OP, ↑IgG4+ plasma cells (>100/HPF) & ↑IgG4/IgG ratio (>70%)

  13. IgG4-related Lung Disease: Focal

  14. IgG4-related Lung Disease: Focal

  15. IgG4-related Lung Disease: Focal IgG4 stain >100 IgG+/hpf >70% IgG4+/IgG+

  16. IgG4-related Lung Disease: ILD 83F (2010) cough, DOE x 2 mo Serum IgG4 215 mg/dL

  17. IgG4-related Lung Disease: ILD 83F

  18. IgG4-related Lung Disease: ILD

  19. IgG4-related Lung Disease: ILD Vascular inflammation

  20. IgG4-related Lung Disease: ILD Storiform fibrosis Plasma cells

  21. IgG4-related Lung Disease: ILD IgG4 stain >30 IgG4+/hpf

  22. 83F 7/10 9/10 Prednisone 30mg/d

  23. IgG4-related Lung Disease: ILD 59M - ILD (Inoue. Radiol 2009)

  24. IgG4-related Mediastinitis and Lymphadenopathy 59M cough, dyspnea, weight loss

  25. IgG4-related Mediastinitis and Lymphadenopathy Oct. 2010 Jan. 2011 59M

  26. IgG4-related Pleuritis 70M AIP

  27. IgG4-related Airway Disease 63F with AIP, cough; serum IgG4 = 2,889 mg/dL (Ito et al. ERJ 2009)

  28. At 1 mo, prednisone (1 mg/kg/d) (Ito et al. ERJ 2009)

  29. Elevated Serum IgG4 Level • IgG4 level >140 mg/dL in 158 of 3,300 patients (4.8%) at Mayo Clinic. • Indication for testing - suspected immunodeficiency in 2/3 of patients. • Only 18% had definite or possible IgG4-RD. Non-IgG4-RD diseases • Respiratory diseases (e.g., bronchiectasis) – 20% • Biliary tract diseases - 17% • Pancreatic diseases – 12% • Cirrhosis & liver dis – 6% • Vasculitis – 6% • Other causes – 3% • No specific diagnosis – 18% (Ryu et al. Int J Rheumatol 2012)

  30. Elevated Serum IgG4 Level (Ryu et al. Int J Rheumatol 2012)

  31. IgG4-positivity on Histopathology • Site-specific unique morphologic features can be seen in some organs. • Lung – airway infiltration, fibrosis lacking storiform pattern. • Histopathologic features may overlap with other fibroinflammatory processes of the lung. • Similar features seen in GPA (Wegener’s). • Increased IgG4+ cells seen in iNSIP, RA-ILD, SLE with DAD, Rosai-Dorfman, etc. (Yi et al. SeminDiagPathol 2012)

  32. Pulmonary Manifestations of IgG4-RDClinical Implications • Wide spectrum of pulmonary manifestations in IgG4-RD. • Many cases of IgG4-RD have gone unrecognized in the past. • Diagnostic criteria are being refined. • Correct diagnosis would reduce unnecessary procedures and morbidity. • IgG4-RD is a treatable disease – corticosteroids, other immunosuppressive agents, rituximab?

  33. “Ancora Imparo.” – (1452-1519)

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