IgG4 Related Disease A Challenge for Pneumonologist
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Pneumonology Department, “Saint Savvas” Anticancer Hospital, Athens, Hellas
Dimitrios Theofilos   

Pneumonology Department, “Saint Savvas” Anticancer Hospital, 171 Alexandras Av., 11522 Athens, Greece
Pneumon 2016;29(2):133–141
IgG4-related disease (IgG4-RD) includes a wide spectrum of inflammatory and fibrous procedures that affect a variety of issues and organs and are accompanied by elevated serum IgG4 levels. The clinical presentation is quite heterogeneous as almost every organ can be influenced. Clinical, laboratory and histopathological features and criteria must be taken into account and both malignancies (solid tumors and lymphomas) and benign disorders be excluded for the diagnosis to be established. Intrathoracic involvement in IgG4-RD varies and includes the lung parenchyma causing nodules, masses, ground-glass opacities, infiltrates resembling consolidation and thickened bronchovascular bundles, the central airways resulting in stenosis, obstruction and bronchiectasis as well as the pleura with effusion and nodular lesions and the mediastinum. Hilar and mediastinal lymphadenopathy are the most common intrathoracic manifestation while fibroid mediastinitis is much more rare. Corticosteroids are the cornerstone of therapy and most of cases present complete or partial response. However, rates of recurrence after treatment termination are high. In addition, patients may develop IgG4-related extrathoracic disease during the next months or even years after the initial diagnosis.
No financial conflicts of interest.
Kamisawa T, Funata N, Hayashi Y et al. A new clinicopathological entity of IgG4-related autoimmune disease. Journal of Gastroenterology 2003;38:982-4.
Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. Journal of Gastroenterology 2006;41:613-25.
Masaki Y, Dong L, Kurose N, et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Annals of the Rheumatic Diseases 2009;68:1310-5.
Yamamoto M, Ohara M, Suzuki C, et al. Elevated IgG4 concentrations in serum of patients with Mikulicz’s disease. Scandinavian journal of Rheumatology 2004;33:432-3.
Okazaki K, Uchida K, Miyoshi H, Ikeura T, Takaoka M, Nishio A. Recent concepts of autoimmune pancreatitis and IgG4-related disease. Clinical Reviews in Allergy & Immunology 2011;41:126-38.
Umehara H, Okazaki K, Masaki Y et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Modern Rheumatology 2012;22:1-4.
Uchida K, Masamune A, Shimosegawa T, Okazaki K. Prevalence of IgG4-related disease in Japan based on nationwide survey in 2009. International Journal of Rheumatology 2012;2012.
Khosroshahi A, Stone JH. A clinical overview of IgG4-related systemic disease. Current Opinion in Rheumatology 2011;23:57-66.
Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. The American Journal of Surgical Pathology 2010;34:1812-9.
Kamisawa T, Shimosegawa T, Okazaki K et al. Standard steroid treatment for autoimmune pancreatitis. Gut 2009;58:1504-7.
Kamisawa T, Okamoto A. IgG4-related sclerosing disease. World J Gastroenterol 2008;14:3948-55.
Sah RP, Chari ST. Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis. Current Opinion in Rheumatology 2011;23:108-13.
Nirula A, Glaser SM, Kalled SL, Taylora FR. What is IgG4? A review of the biology of a unique immunoglobulin subtype. Current Opinion in Rheumatology 2011;23:119-24.
Zen Y, Nakanuma Y. Pathogenesis of IgG4-related disease. Current Opinion in Rheumatology 2011;23:114-8.
Shrestha B, Sekiguchi H, Colby TV, et al. Distinctive pulmonary histopathology with increased IgG4-positive plasma cells in patients with autoimmune pancreatitis: report of 6 and 12 cases with similar histopathology. The American Journal of Surgical Pathology 2009;33:1450-62.
Smyrk TC. Pathological features of IgG4-related sclerosing disease. Current Opinion in Rheumatology 2011;23:74-9.
Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4–associated cholangitis: clinical profile and response to therapy. Gastroenterology 2008;134:706-15.
Naitoh I, Nakazawa T, Ohara H, et al. Clinical significance of extrapancreatic lesions in autoimmune pancreatitis. Pancreas 2010;39:e1-5.
Fujinaga Y, Kadoya M, Kawa S, et al. Characteristic findings in images of extra-pancreatic lesions associated with autoimmune pancreatitis. European Journal of Radiology 2010;76:228-38.
Hamano H, Arakura N, Muraki T, Ozaki Y, Kiyosawa K, Kawa S. Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. Journal of Gastroenterology 2006;41:1197-205.
Stone JH, Khosroshahi A, Deshpande V, Stone JR. IgG4‐related systemic disease accounts for a significant proportion of thoracic lymphoplasmacytic aortitis cases. Arthritis Care & Research 2010;62:316-22.
Cheuk W, Yuen HK, Chu SY, Chiu EK, Lam LK, Chan JK. Lymphadenopathy of IgG4-related sclerosing disease. The American Journal of Surgical Pathology 2008;32:671-81.
Zen Y, Inoue D, Kitao A, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. The American Journal of Surgical Pathology 2009;33:1886-93.
Tsushima K, Tanabe T, Yamamoto H, et al. Pulmonary involvement of autoimmune pancreatitis. European Journal of Clinical Investigation 2009;39:714-22.
Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4–related Lung Disease: CT Findings with Pathologic Correlations 1. Radiology 2009;251:260-70.
Umehara H, Okazaki K, Masaki Y et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Modern Rheumatology 2012;22:21-30.
Ebbo M, Grados A, Bernit E, et al. Pathologies associated with serum IgG4 elevation. International Journal of Rheumatology 2012;2012.
Carruthers MN, Khosroshahi A, Augustin T, Deshpande V, Stone JH. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Annals of the Rheumatic Diseases 2015;74:14-8.
Ngwa TN, Law R, Murray D, Chari ST. Serum Immunoglobulin G4 Level Is a Poor Predictor of Immunoglobulin G4–Related Disease. Pancreas 2014;43:704-7.
Deshpande V. The pathology of IgG4-related disease: critical issues and challenges. In Seminars in Diagnostic Pathology 2012 (Vol. 29, No. 4, pp. 191-196). WB Saunders.
Takahashi H, Yamamoto M, Tabeya T, et al. The immunobiology and clinical characteristics of IgG4 related diseases. Journal of Autoimmunity 2012;39:93-6.
Kawano M, Mizushima I, Yamaguchi Y, et al. Immunohistochemical characteristics of IgG4-related tubulointerstitial nephritis: detailed analysis of 20 Japanese cases. International Journal of Rheumatology 2012;2012.
Della Torre E, Mattoo H, Mahajan VS, Carruthers M, Pillai S, Stone JH. Prevalence of atopy, eosinophilia, and IgE elevation in IgG4‐related disease. Allergy 2014;69:269-72.
Okazaki K, Umehara H. Are classification criteria for IgG4-RD now possible? The concept of IgG4-related disease and proposal of comprehensive diagnostic criteria in Japan. International Journal of Rheumatology 2012;2012.
Shigemitsu H, Koss MN. IgG4-related interstitial lung disease: a new and evolving concept. Current Opinion in Pulmonary Medicine 2009;15:513-6.
Duvic C, Desrame J, Lévêque C, Nedelec G. Retroperitoneal fibrosis, sclerosing pancreatitis and bronchiolitis obliterans with organizing pneumonia. Nephrology Dialysis Transplantation 2004;19:2397-9.
Yamashita K, Haga H, Kobashi Y, Miyagawa-Hayashino A, Yoshizawa A, Manabe T. Lung involvement in IgG4-related lymphoplasmacytic vasculitis and interstitial fibrosis: report of 3 cases and review of the literature. The American Journal of Surgical Pathology 2008;32:1620-6.
Kobayashi H, Shimokawaji T, Kanoh S, Motoyoshi K, Aida S. IgG4-positive pulmonary disease. Journal of Thoracic Imaging 2007;22:360-2.
Hirano K, Kawabe T, Komatsu Y et al. High‐rate pulmonary involvement in autoimmune pancreatitis. Internal Medicine Journal 2006;36:58-61.
Taniguchi T, Hamasaki A, Okamoto M. A case of suspected lymphocytic hypophysitis and organizing pneumonia during maintenance therapy for autoimmune pancreatitis associated with autoimmune thrombocytopenia. Endocrine Journal 2006;53:563-6.
Ohara H, Nakazawa T, Sano H, et al. Systemic extrapancreatic lesions associated with autoimmune pancreatitis. Pancreas 2005;31:232-7.
Zen Y, Kitagawa S, Minato H, et al. IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung. Human Pathology 2005;36:710-7.
Tanaka K, Nagata K, Tomii K, Imai Y. A case of isolated IgG4- related interstitial pneumonia: a new consideration for the cause of idiopathic nonspecific interstitial pneumonia. CHEST Journal 2012;142:228-30.
Eunhee SY, Sekiguchi H, Peikert T, Ryu JH, Colby TV. Pathologic manifestations of Immunoglobulin (Ig) G4-related lung disease. In Seminars in Diagnostic Pathology 2012 (Vol. 29, No. 4, pp. 219-225). WB Saunders.
Masaki Y, Kurose N, Yamamoto M, et al. Cutoff values of serum IgG4 and histopathological IgG4. International Journal of Rheumatology 2012;2012.
Kato E, Takayanagi N, Ishiguro T, Kagiyama N, Shimizu Y, Sugita Y. IgG4-related pleuritis with chylothorax. Internal Medicine 2014;53:1545-8.
Goag EK, Park JE, Lee EH, et al. A Case of Extensive IgG4-Related Disease Presenting as Massive Pleural Effusion, Mediastinal Mass, and Mesenteric Lymphadenopathy in a 16-Year-Old Male. Tuberculosis and Respiratory Diseases 2015;78:396-400.
Sato Y, Yoshino T. IgG4-related lymphadenopathy. International Journal of Rheumatology 2012;2012.
Grimm KE, Barry TS, Chizhevsky V, et al. Histopathological findings in 29 lymph node biopsies with increased IgG4 plasma cells. Modern Pathology 2012;25:480-91.
Nakajo M, Jinnouchi S, Fukukura Y, Tanabe H, Tateno R, Nakajo M. The efficacy of whole-body FDG-PET or PET/CT for autoimmune pancreatitis and associated extrapancreatic autoimmune lesions. European Journal of Nuclear Medicine and Molecular Imaging 2007;34:2088-95.
Hamed G, Tsushima K, Yasuo M et al. Inflammatory lesions of the lung, submandibular gland, bile duct and prostate in a patient with IgG4‐associated multifocal systemic fibrosclerosis. Respirology 2007;12:455-7.
Flieder DB, Suster S, Moran CA. Idiopathic fibroinflammatory (fibrosing/sclerosing) lesions of the mediastinum: a study of 30 cases with emphasis on morphologic heterogeneity. Modern pathology: an Official Journal of the United States and Canadian Academy of Pathology, Inc. 1999;12:257-64.
Rossi SE, McAdams HP, Rosado-de-Christenson ML, Franks TJ, Galvin JR. Fibrosing Mediastinitis 1. Radiographics 2001;21:737-57.
Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine 1988;67:295- 310.
Straus SE, Jacobson ES. The spectrum of histoplasmosis in a general hospital: a review of 55 cases diagnosed at Barnes Hospital between 1966 and 1977. The American Journal of the Medical Sciences 1980;279:147-58.
Carruthers MN, Stone JH, Khosroshahi A. The latest on IgG4-RD: a rapidly emerging disease. Current Opinion in Rheumatology 2012;24:60-9.
Theofilos D, Triantafillidou C, Zetos A et al. A 44-Year-Old Man With Chronic Cough, Weakness, and a Mediastinum Mass. CHEST Journal 2015;148:e86-90.
Inoue M, Nose N, Nishikawa H, Takahashi M, Zen Y, Kawaguchi M. Successful treatment of sclerosing mediastinitis with a high serum IgG4 level. General Thoracic and Cardiovascular Surgery 2007;55:431-3.
Peikert T, Shrestha B, Aubry MC, et al. Histopathologic overlap between fibrosing mediastinitis and IgG4-related disease. International Journal of Rheumatology 2012;2012.
Strehl JD, Hartmann A, Agaimy A. Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders. Journal of Clinical Pathology 2011:jcp-2010.
Yamamoto M, Takahashi H, Suzuki C et al. Analysis of serum IgG subclasses in churg-strauss syndrome-The meaning of elevated serum levels of IgG4. Internal Medicine 2010;49:1365-70.
Ito M, Yasuo M, Yamamoto H, et al. Central airway stenosis in a patient with autoimmune pancreatitis. ERJ 2009;33:680-3.
Khan ML, Colby TV, Viggiano RW, Fonseca R. Treatment with bortezomib of a patient having hyper IgG4 disease. Clinical Lymphoma Myeloma and Leukemia 2010;10:217-9.
Takato H, Yasui M, Ichikawa Y, et al. Nonspecific interstitial pneumonia with abundant IgG4-positive cells infiltration, which was thought as pulmonary involvement of IgG4-related autoimmune disease. Internal Medicine 2008;47:291-4.
Khosroshahi A, Bloch DB, Deshpande V, Stone JH. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4‐related systemic disease. Arthritis & Rheumatism 2010;62:1755-62.
Takahashi N, Ghazale AH, Smyrk TC, Mandrekar JN, Chari ST. Possible association between IgG4-associated systemic disease with or without autoimmune pancreatitis and non-Hodgkin lymphoma. Pancreas 2009;38:523-6.
Fukui T, Mitsuyama T, Takaoka M, Uchida K, Matsushita M, Okazaki K. Pancreatic cancer associated with autoimmune pancreatitis in remission. Internal Medicine 2008;47:151-5.